Fused pyrimidines as inhibitors of p97 complex

ABSTRACT

The present invention is directed to certain fused pyrimidines having a homo or hetero cyclopentyl, cyclohexyl or cycloheptyl ring as the pyrimidine fusion partner, having an amino benzyl or substituted amino benzyl group at the 4 position of the pyrimidine ring; and a 5:6 heterobicyclo ring with at least one N, O or S at the 2 position of the pyrimidine ring. These compounds are useful for treatment of cancer by inhibition of the p97 complex.

BACKGROUND OF THE INVENTION

The AAA (ATPase Associated with a variety of Activities) ATPase p97having the descriptive name, Valosin containing protein, is conservedacross all eukaryotes and is essential for life in budding yeast(Giaever, G., et. al. Nature (2002) 418, 387-391) and mice (Muller, J.M. et al. Biochem. Biophys. Res. Commun. (2007) 354, 459-465). Humansbearing reduction-of-function alleles of p97 are afflicted with asyndrome that includes inclusion body myopathy and frontotemporal lobardegeneration (Weihi. C, et al. Hum. Mol. Genet. (2006) 15, 189-199).Loss-of-function studies in model organisms indicate that p97 plays acritical role in a broad array of cellular processes including Golgimembrane reassembly (Rahouille, C. et al. Cell (1995) 82, 905-914),membrane transport (Ye, Y. et al Nature (2001) 414, 652-656; Ye. Y, eal. Nature (2004) 429, 841-847) degradation of misfolded membrane andsecretory proteins by the ubiquitin-proteasome system (UPS) (Golbik, R.et al. Biol. Chem. (1999) 380, 1049-1062; Richly, H. et al. Cell (2005)120, 73-84), regulation of myofibril assembly (Janiesch, P. C. et al.Nat. Cell Biol. (2007) 9, 379-390), and cell division (Cao, K. et al.Cell (2003) 115, 355-367). The broad range of cellular functions forthis protein is thought to derive from its ability to unfold proteins ordisassemble protein complexes. The mechanochemical activity of p97 islinked to substrate proteins by an array of at least 14 UBX domainadapters that bind p97, as well as the non-UBX domain adaptors Ufd1 andNp14 (Meyer, H. H. et al. EMBO J. (2000) 19, 2181-2192).

The sequence of p97 reveals three domains (N-domain, D1 ATPase domain,and D2 ATPase domain) joined by linker regions. X-ray crystallography ofp97 revealed that it forms a homohexamer of 97 kilodalton subunits thatassemble to form two stacked rings. The two rings are formed by theATPase domains (Huyton, T. et al., Struct. Biol. (2003) 144, 337-348;DeLaBarre, B. et al. Nat. Struct. Biol. (2003) 10, 856-863). The ‘top’ring is formed by a hexamer of the D1 domains, whereas the ‘bottom’ ringis formed by a hexamer of the D2 domains. The N-domain extends outwardfrom the D1 domain ring. Although it is clear that the D2 domainhydrolyzes ATP in vitro, the level of D1-specific ATPase activityreported by different investigators varies. Nevertheless, geneticstudies in yeast suggest that ATP hydrolysis by both the D1 and D2domains is essential for the function of p97 (Song, C. et al. J. Biol.Chem. (2003) 278, 3648-3655; Ye, Y. et al. J. Cell Biol. (2004) 162,71-84). Binding of ATP to the D1 domain is also required for assembly ofp97 (Wang, Q. et al. Biochem. Biophys. Res. Commun. (2003) 300,253-260). Although ATP hydrolysis by the D2 domain is not required forassembly of p97 hexamer, it is thought that ATP hydrolysis by the D2domain is a substrate conversion, resulting in their unfolding ordissociation from bound partners.

A prominent cellular function for p97 that has received considerablescrutiny is its role in the turnover of misfolded secretory proteins viathe UPS (ubiquitin proteasome system). In this process, which is knownas ERAD (for endoplasmic reticulum-associated degradation), proteinsthat fail to fold within the ER are retrotranslocated in a p97-dependentmanner into the cytoplasm where they are degraded by the UPS (Ye, Y. etal. Nature (2004) 429, 841-847). In this process, p97 is thought tomediate extraction of substrates from the ER membrane. The complex p97is also required for the turnover of cytosolic substrates of the UPS(Janiesch, P. C. et al. Nat. Cell Biol. (2007) 9, 379-390; Cao, K. etal. Cell (2003) 115, 355-367; Fu. X. et al. J. Cell Biol. (2003) 163,21-26), although its role in turnover of cytosolic proteins is lessunderstood.

The Valosin containing protein, p97, represents a suitable target forcancer therapeutics. The complex p97 and its function are essential forcontinued cellular viability, and so drugs that inhibit it should beantiproliferative. In other words, inhibition of p97 will causeundesirable protein concentration within the target cell. Aconsequential cellular reaction is often apoptosis or at leastamelioration of cellular growth and mitosis. Also, p97 is known to beoverproduced in multiple cancers (Yamamoto, S. et al. Ann. Surg. Oncol.(2005) 12, 925-934; Yamamoto, S. et al. Clin. Cancer Res. (2004) 10,5558-5565; Yamamoto. S. et al. Ann. Surg. Oncol. (2004) 11, 697-704;Yamamoto. S. et al. Ann. Surg. Oncol. (2004) 11, 165-172) suggestingthat its activity may be rate-limiting for the development of at leastsome cancers. p97 is known to be essential for ERAD (Carvalho. P. et al.Cell (2006) 126, 361-373), and recent studies suggest that cancer cellsmay be particularly dependent upon ERAD (Boelens, J. et al. In Vivo(2007) 21, 215-226). Furthermore, p97 has been linked to the turnover ofIIcB and consequent activation of NF-kB (Dai. R. M. et al. J. Biol.Chem. (1998) 273, 3562-3573). NF-kB activity is important for thesurvival of some tumor cells, particularly in multiple myeloma (Keats,J. J. et. al. Cancer Cell (2007) 12, 131-144; Annunziata, C. M. et. al.Cancer Cell (2007) 12, 115-130). It has been suggested that bortezomibis active in multiple myloma due to its ability to block turnover ofproteins via the ERAD pathway and its ability to block turnover of 1 kB,thereby squelching the activity of NF-kB. Given that p97 is implicatedin both ERAD and IIcB turnover but otherwise has a more restricted rolein the UPS compared to the proteasome itself, drugs that target p97 mayretain much of the efficacy of bortezomib but with less toxicity. Inaddition, compounds intersecting with the p97 complex are disclosed inPCT/US2011/035654, filed May 6, 2011 and published as WO2011/140527 onNov. 10, 2011.

GOALS OF THE INVENTION

Thus, there is a need to develop compounds suitable for inhibition ofp97 activity and for methods of inhibiting the activity of p97 usingsuch compounds. There is a need to develop such compounds for use intreatment of neoplastic malconditions.

SUMMARY OF THE INVENTION

These and other needs are met by aspects of the present invention, oneof which is directed to a group of fused pyrimidine compounds having acyclopentyl, cyclohexyl or cycloheptyl ring as the fusion partner of thefused pyrimidine compounds. The fusion partner optionally contains anitrogen, oxygen or sulfur heteroatom in its ring. The fused pyrimidinecompounds have certain optionally substituted 5:6 heterocyclic ringssubstituted at the 2 position of the pyrimidine ring and an optionallysubstituted benzyl amine group substituted at the 4 position of thepyrimidine ring.

In a further aspect of the invention, the fused pyrimidine of theinvention and their pharmaceutical compositions have an ability toinhibit Valosin containing protein p97 and to ameliorate, diminish,shrink, moderate and/or eliminate cells exhibiting neoplastic tendenciesand/or abnormal function. In a further aspect of the invention, suchcompounds and compositions inhibit the ATPase activity of p97. Anotheraspect of the invention concerns treatment of malconditions and/ordisease such as cancer through use of such compounds and compositions.

The first aspect of the invention is directed to fused pyrimidinecompounds having a 5:6 heterocyclic ring at position 2 of the pyrimidinering and an optionally substituted benzyl amine group at position 4 ofthe pyrimidine ring. Embodiments of the fused pyrimidine compounds ofthe invention have a structure represented by Formula I wherein Y isCR⁴, NH, NR⁵, O or S and C of CR⁴ is an sp³ carbon. The symbols m and nof Formula I are each independently an integer of 0, 1, 2, 3 or 4 andthe sum of n and m is an integer of 2, 3 or 4. Ar is an optionallysubstituted aryl group and the moiety at the 2 position of thepyrimidine ring is a 5:6 heterobicyclic ring herein designated as HET.

The “scaffold” of Formula I is the fused pyrimidine ring alone and isrepresented by Formula II. Formula II presents embodiments of the fusedpyrimidine ring without the -HET and —NHCH₂Ar moieties. The scaffold(Formula II) is a fused pyrimidine in which the saturated ring fused tothe pyrimidine is a 5, 6 or 7 membered ring and the Y group or atom isin any position around the saturated ring except at the positions sharedby the pyrimidine ring. Preferred saturated rings of the scaffold arethe five and six membered saturated rings in which Y is located at anyposition around the saturated ring except the fusion positions.Preferred locations of Y on the five and six membered saturated ringsare the saturated ring positions adjacent to the fused positions.Further preferred scaffolds are the 5 and 6 membered saturated ringswherein Y is located at saturated ring positions other than adjacent tothe fusion positions and when Het is other than an indole orbenzimidazole moiety.

The HET moiety of Formula I is represented by Formula HET wherein A, D,E, B and Z have the following designations. The following designationsof A, D, E. B and Z also apply to the embodiments of the fusedpyrimidine compounds of the invention represented by Formula I. The sixmembered ring of Formula IIET is an aromatic ring while the fivemembered ring may be aromatic or partially saturated.

A, D and E of Formula HET (and hence of Formula I) are eachindependently C or N wherein C is an sp² carbon substituted by H oralkyl of one to four carbons when one of the C valences is not otherwisedesignated. Z and B are each independently CR⁶, N, NR⁷, O or S wherein Cas CR⁶ is an sp³ carbon.

Certain provisos apply to Formula IIET when part of Formula I. Theseare:

-   -   1. At least one of D and E is C:    -   2. At least one of A, D, E, Z and B is other than C;    -   3. Z and B cannot both simultaneously be any of NR⁷, O or S;    -   4. When one of D and E is N and A is C, then Z and B are each        independently CR⁶, N or NR^(7;)    -   5. When both of D and E are C and A is N, then Z and B are each        independently CR⁶ or N; and in this designation for D, E, A. Z        and B, when Y is carbon and R³ is hydrogen, or in this        designation for D, E, A, Z and B when both of m and n are other        than 0 (zero integer), then in either of these sub-designations,        Z and B cannot both be CR⁶ and B cannot be N;    -   6. When all of D, E and A are C, then Z and B are each        independently CR⁶, N, NR⁷, O or S;    -   7. When one of Z and B is O or S, then the other is CR⁶ or N,        and A, D and E are all C;    -   8. When one of Z and B is NR⁷, then the other is N or CR⁶ and A,        D and E are all C.

For proviso 5, a single primary designation and two secondarydesignations are present. When both of D and E are C and A is N, thenthe primary designation is that Z and B are each independently CR⁶ or N.Under this primary designation, two secondary designations apply. Underthe primary designation for Z and B when D and E are C and A is N, thefirst secondary designation is that when Y is carbon and the R³ groupattached to Y as C is hydrogen, then Z and B cannot both be CR⁶ and Bcannot be N. Also, under the primary designation for Z and B when D andE are C and A is N, the second secondary designation is that when bothof m and n are other than 0 (i.e., m and n are independently an integerof 1-4) and R³ is hydrogen, then Z and B cannot both be CR⁶ and B cannotbe N.

The substituents R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ may be each independentlyselected from hydrogen, an optionally substituted aliphatic group, anoptionally substituted aromatic group and/or an optionally substitutedfunctional group.

These designations of the substituent R groups are further described inthe definition section below.

An additional aspect of the invention is directed to a pharmaceuticalcomposition of a pharmaceutically acceptable carrier and the abovedescribed compounds of Formula I.

Another aspect of the invention is directed to a method of decreasingValosin containing protein (p⁹⁷) activity or decreasing degradation of aproteasome system substrate, especially a ubiquitin substrate, byadministration to a patent in need an effective therapeutic amount ofthe one of the compounds of Formula I.

Yet another aspect of the invention is directed to the treatment ofneoplastic malconditions, cancer and other malconditions associated withp97 by administration to a patient in need a compound of Formula I orthe foregoing pharmaceutical composition.

The fused pyrimidine compounds and pharmaceutical compositions of theinvention will inhibit or ameliorate the activity of the bioactiveenzyme p97, show the physiological profile and will preferably show thedesirable degree of inhibition or amelioration, especially with respectto the treatment of cancer and related malconditions.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by a person of ordinaryskill in the art.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

The term “about” as used herein, when referring to a numerical value orrange, allows for a degree of variability in the value or range, forexample, within 10%, or within 5% of a stated value or of a stated limitof a range.

All percent compositions are given as weight-percentages, unlessotherwise stated.

All average molecular weights of polymers are weight-average molecularweights, unless otherwise specified.

As used herein, “individual” (as in the subject of the treatment) or“patient” means both mammals and non-mammals. Mammals include, forexample, humans; non-human primates, e.g. apes and monkeys; andnon-primates, e.g. dogs, cats, cattle, horses, sheep, and goats.Non-mammals include, for example, fish and birds.

The term “may” in the context of this application means “is permittedto” or “is able to” and is a synonym for the term “can.” The term “may”as used herein does not mean possibility or chance.

The term “disease” or “disorder” or “malcondition” are usedinterchangeably, and are used to refer to diseases or conditions whereinX plays a role in the biochemical mechanisms involved in the disease ormalcondition or symptom(s) thereof such that a therapeuticallybeneficial effect can be achieved by acting on X. “Acting on” X, or“modulating” X, can include binding to X and/or inhibiting thebioactivity of X and/or allosterically regulating the bioactivity of Xin vivo.

The expression “effective amount”, when used to describe therapy to anindividual suffering from a disorder, refers to the amount of a drug,pharmaceutical agent or compound of the invention that will elicit thebiological or medical response of a cell, tissue, system, animal orhuman that is being sought, for instance, by a researcher or clinician.Such responses include but are not limited to amelioration, inhibitionor other action on a disorder, malcondition, disease, infection or otherissue with or in the individual's tissues wherein the disorder,malcondition, disease and the like is active, wherein such inhibition orother action occurs to an extent sufficient to produce a beneficialtherapeutic effect. Furthermore, the term “therapeutically effectiveamount” means any amount which, as compared to a corresponding subjectwho has not received such amount, results in improved treatment,healing, prevention, or amelioration of a disease, disorder, or sideeffect, or a decrease in the rate of advancement of a disease ordisorder. The term also includes within its scope amounts effective toenhance normal physiological function.

“Substantially” as the term is used herein means completely or almostcompletely; for example, a composition that is “substantially free” of acomponent either has none of the component or contains such a traceamount that any relevant functional property of the composition isunaffected by the presence of the trace amount, or a compound is“substantially pure” is there are only negligible traces of impuritiespresent.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder, or curing thedisease or disorder. Similarly, as used herein, an “effective amount” ora “therapeutically effective amount” of a compound of the inventionrefers to an amount of the compound that alleviates, in whole or inpart, symptoms associated with the disorder or condition, or halts orslows further progression or worsening of those symptoms, or prevents orprovides prophylaxis for the disorder or condition. In particular, a“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result. A therapeutically effective amount is also one inwhich any toxic or detrimental effects of compounds of the invention areoutweighed by the therapeutically beneficial effects.

Phrases such as “under conditions suitable to provide” or “underconditions sufficient to yield” or the like, in the context of methodsof synthesis, as used herein refers to reaction conditions, such astime, temperature, solvent, reactant concentrations, and the like, thatare within ordinary skill for an experimenter to vary, that provide auseful quantity or yield of a reaction product. It is not necessary thatthe desired reaction product be the only reaction product or that thestarting materials be entirely consumed, provided the desired reactionproduct can be isolated or otherwise further used.

By “chemically feasible” is meant a bonding arrangement or a compoundwhere the generally understood rules of organic structure are notviolated; for example a structure within a definition of a claim thatwould contain in certain situations a pentavalent carbon atom that wouldnot exist in nature would be understood to not be within the claim. Thestructures disclosed herein, in all of their embodiments are intended toinclude only “chemically feasible” structures, and any recitedstructures that are not chemically feasible, for example in a structureshown with variable atoms or groups, are not intended to be disclosed orclaimed herein.

An “analog” of a chemical structure, as the term is used herein, refersto a chemical structure that preserves substantial similarity with theparent structure, although it may not be readily derived syntheticallyfrom the parent structure. A related chemical structure that is readilyderived synthetically from a parent chemical structure is referred to asa “derivative.”

When a substituent is specified to be an atom or atoms of specifiedidentity. “or a bond”, a configuration is referred to when thesubstituent is “a bond” that the groups that are immediately adjacent tothe specified substituent are directly connected to each other in achemically feasible bonding configuration.

All chiral, diastereomeric, racemic forms of a structure are intended,unless a particular stereochemistry or isomeric form is specificallyindicated. In several instances though an individual stereoisomer isdescribed among specifically claimed compounds, the stereochemicaldesignation does not imply that alternate isomeric forms are lesspreferred, undesired, or not claimed. Compounds used in the presentinvention can include enriched or resolved optical isomers at any or allasymmetric atoms as are apparent from the depictions, at any degree ofenrichment. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers can be isolated or synthesized so as to besubstantially free of their enantiomeric or diastereomeric partners, andthese are all within the scope of the invention.

As used herein, the terms “stable compound” and “stable structure” aremeant to indicate a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into an efficacious therapeutic agent. Only stable compoundsare contemplated herein.

Selected substituents within the compounds described herein are presentto a recursive degree. In this context, “recursive substituent” meansthat a substituent may recite another instance of itself. Because of therecursive nature of such substituents, theoretically, a large number maybe present in any given claim. One of ordinary skill in the art ofmedicinal chemistry and organic chemistry understands that the totalnumber of such substituents is reasonably limited by the desiredproperties of the compound intended. Such properties include, by ofexample and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis. Recursive substituents are an intended aspect of thedisclosed subject matter. One of ordinary skill in the art of medicinaland organic chemistry understands the versatility of such substituents.To the degree that recursive substituents are present in a claim of thedisclosed subject matter, the total number should be determined as setforth above.

When a group is recited, wherein the group can be present in more than asingle orientation within a structure resulting in more than singlemolecular structure, e.g., a carboxamide group C(═O)NR, it is understoodthat the group can be present in any possible orientation, e.g.,X—C(═O)N(R)—Y or X—N(R)C(═O)—Y, unless the context clearly limits theorientation of the group within the molecular structure.

When a group, e.g., an “alkyl” group, is referred to without anylimitation on the number of atoms in the group, it is understood thatthe claim is definite and limited with respect the size of the alkylgroup, both by definition; i.e., the size (the number of carbon atoms)possessed by a group such as an alkyl group is a finite number, lessthan the total number of carbon atoms in the universe and bounded by theunderstanding of the person of ordinary skill as to the size of thegroup as being reasonable for a molecular entity; and by functionality,i.e., the size of the group such as the alkyl group is bounded by thefunctional properties the group bestows on a molecule containing thegroup such as solubility in aqueous or organic liquid media. Therefore,a claim reciting an “alkyl” or other chemical group or moiety isdefinite and bounded, as the number of atoms in the group cannot beinfinite.

In general, “substituted” refers to an organic group as defined hereinin which one or more bonds to a hydrogen atom contained therein arereplaced by one or more bonds to a non-hydrogen atom. More particularly,the term “chemical substituent” refers to any and all aliphatic,aromatic and functional groups listed in this section that can beappended to an organic molecule. A functional group is an inorganicmoiety such as halogen, sulfate, nitro, amino and the like as well asmonocarbon functional groups such as carboxyl, carbonyl, carboxamidethat are ordinary and typical optional substituents of organicmolecules. In the context of this invention, recitation of this termwithout indication of specific groups constitutes the definition givenabove. Recitation of this term in combination with a Markush recitationof specific groups constitutes a suhgenus of the understanding conveyedby the foregoing definition. The term “substituent” generally means anyappropriate group named below that has an “yl”, “y” or “o” ending todesignate that it is appended, attached or covalently bonded to anothermoiety such as but not limited to an aromatic framework. Examplesinclude but are not limited to, a halogen (i.e., F, Cl, Br, and I); anoxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxygroups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groupsincluding carboxylic acids, carboxylates, and carboxylate esters; asulfur atom in groups such as thiol groups, alkyl and aryl sulfidegroups, sulfoxide groups, sulfone groups, sulfonyl groups, andsulfonamide groups; a nitrogen atom in groups such as amines,hydroxylamnines, nitriles, nitro groups, N-oxides, hydrazides, azides,and enamines; and other heteroatoms in various other groups.

When a substituent is monovalent, such as, for example, F or Cl, it isbonded to the atom it is substituting by a single bond. When asubstituent is more than monovalent, such as O, which is divalent, itcan be bonded to the atom it is substituting by more than one bond,i.e., a divalent substituent is bonded by a double bond; for example, aC substituted with O forms a carbonyl group, C═O, which can also bewritten as “CO”, “C(O)”, or “C(═O)”, wherein the C and the O are doublebonded. When a carbon atom is substituted with a double-bonded oxygen(═O) group, the oxygen substituent is termed an “oxo” group. When adivalent substituent such as NR is double-bonded to a carbon atom, theresulting C(═NR) group is termed an “imino” group. When a divalentsubstituent such as S is double-bonded to a carbon atom, the resultsC(═S) group is termed a “thiocarbonyl” or “thiono” group.

Alternatively, a divalent substituent such as O or S can be connected bytwo single bonds to two different carbon atoms. For example, O, adivalent substituent, can be bonded to each of two adjacent carbon atomsto provide an epoxide group, or the O can form a bridging ether group,termed an “oxy” group, between adjacent or non-adjacent carbon atoms,for example bridging the 1,4-carbons of a cyclohexyl group to form a[2.2.1]-oxabicyclo system. Further, any substituent can be bonded to acarbon or other atom by a linker, such as (CH₂) or (CR′₂)_(n) wherein nis 1, 2, 3, or more, and each R′ is independently selected.

For all substituents, the first atom of the molecular formula of thesubstituent is the atom bonding the substituent to its correspondingmoiety, eg, for the functional group, N(R^(a))C(O)R^(a), the N is bondedto the corresponding moiety substituted by this group. If thesubstituent is described in words, such as alkyenylamine, the phraseending in “enyl” indicates the carbon atom bonding the substituent toits corresponding moiety. For substituents that display a single bondingsite, such as carboxylic acid, sulfonic acid, fluoro, methyl and thelike, the bonding arrangement is the expected arrangement.

“Aliphatic substituent, group or component” refers to any organic groupthat is non-aromatic. Included are acyclic and cyclic organic compoundscomposed of carbon, hydrogen and optionally of oxygen, nitrogen, sulfurand other heteroatoms. This term encompasses all of the followingorganic groups except the following defined aromatic and heteroaromaticgroups. Examples of such groups include but are not limited to alkyl,alkenyl, alkynyl, corresponding groups with heteroatoms, cyclic analogs,heterocyclic analogs, branched and linear versions and such groupsoptionally substituted with functional groups, as these groups andothers meeting this definition of“aliphatic” are defined below.

“Aromatic substituent, group or component” refers to any and allaromatic groups including but not limited to aryl, aralkyl,heteroalkylaryl, heteroalkylheteroaryl and heteroaryl groups. The term“aromatic” is general in that it encompasses all compounds containingaryl groups optionally substituted with functional groups (all carbonaromatic groups) and all compounds containing heteroaryl groupsoptionally substituted with functional groups (carbon-heteroatomaromatic groups), as these groups and others meeting this definition of“aromatic” are defined below.

As used herein, the term “optionally” means that the correspondingsubstituent or thing may or may not be present. It includes bothpossibilities.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., C₁-C₁₀ alkyl).Whenever it appears herein, a numerical range such as “1 to 10” refersto each integer in the given range; e.g., “1 to 10 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated. In some embodiments, it is a C₁-C₄alkyl group. Typical alkyl groups include, but are in no way limited to,methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butylisobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl,octyl, nonyl, decyl, and the like. The alkyl is attached to the rest ofthe molecule by a single bond, for example, methyl (Me), ethyl (Et),n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.

Unless stated otherwise specifically in the specification, an alkylgroup is optionally substituted by one or more of substituents asdefined above. Such substituents further independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR, —N(R)C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂ whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl areas disclosed herein and which are optionally substituted by one or moreof the substituents described as suitable substituents for aryl andalkyl respectively.

“Alkylhetaryl” refers to an -(alkyl)hetaryl radical where hetaryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively.

“Alkylheterocycloalkyl” refers to an -(alkyl) heterocycyl radical wherealkyl and heterocycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heterocycloalkyl and alkyl respectively.

An “alkene” moiety refers to a group consisting of at least two carbonatoms and at least one carbon-carbon double bond, and an “alkyne” moietyrefers to a group consisting of at least two carbon atoms and at leastone carbon-carbon triple bond. The alkyl moiety, whether saturated orunsaturated, may be branched, straight chain, or cyclic.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (i.e.,C₂-C₁₀ alkenyl). Whenever it appears herein, a numerical range such as“2 to 10” refers to each integer in the given range; e.g., “2 to 10carbon atoms” means that the alkenyl group may consist of 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to five carbon atoms (e.g.,C₂-C₅ alkenyl). The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

Unless stated otherwise specifically in the specification, an alkenylgroup is optionally substituted by one or more substituents as definedabove. Such substituents further independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R²)C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a)(where t is 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2),—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, where each R^(a)is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkenyl-cycloalkyl” refers to an -(alkenyl)cycloalkyl radical wherealkenyl and cyclo alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituens for alkenyl and cycloalkyl respectively.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (i.e., C2-C10alkynyl). Whenever it appears herein, a numerical range such as “2 to10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkynyl group may consist of 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkynyl comprises two to eight carbon atoms. In otherembodiments, an alkynyl has two to five carbon atoms (e.g., C2-C5alkynyl). The alkynyl is attached to the rest of the molecule by asingle bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,and the like.

Unless stated otherwise specifically in the specification, an alkynylgroup is optionally substituted by one or more substituents as definedabove. Such substituents further independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))2, —C(O)R^(a), —C(O)OR, —C(O)N(R^(a))2,—C(O)N(R^(a))2, —N(R)C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))2, N(R^(a))C(NR^(a))N(R^(a))2,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))2 (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkynyl-cycloalkyl” refers to refers to an -(alkynyl)cycloalkyl radicalwhere alkynyl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for alkynyl and cycloalkyl respectively.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl” refers to a monocyclic or polycyclic radical that containsonly carbon and hydrogen, and may be saturated, or partiallyunsaturated.

Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e.,C₂-C₁ cycloalkyl). Whenever it appears herein, a numerical range such as“3 to 10” refers to each integer in the given range; e.g., “3 to 10carbon atoms” means that the cycloalkyl group may consist of 3 carbonatoms, etc., up to and including 10 carbon atoms. In some embodiments,it is a C₃-C₈ cycloalkyl radical. In some embodiments, it is a C₃-C₅,cycloalkyl radical. Illustrative examples of cycloalkyl groups include,but are not limited to the following moieties: cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl,cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.

Unless stated otherwise specifically in the specification, a cycloalkylgroup is optionally substituted by one or more substituents as definedabove. Such substituents further independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethyl silanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)N(R^(a))₂ (where t is 1 or 2), or PO₃(R)₂, where eachR^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Cycloalkyl-alkenyl” refers to a -(cycloalkyl) alkenyl radical wherecycloalkyl and heterocycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heterocycloalkyl and cycloalkyl respectively.

“Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl) heterocycylradical where cycloalkyl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heterocycloalkyl and cycloalkylrespectively.

“Cycloalkyl-heteroaryl” refers to a -(cycloalkyl) heteroaryl radicalwhere cycloalkyl and heterocycloalkyl are as disclosed herein and whichare optionally substituted by one or more of the substituents describedas suitable substituents for heterocycloalkyl and cycloalkylrespectively.

“Alkoxy” refers to the group —O-alkyl, including from 1 to 8 carbonatoms of a straight, branched, cyclic configuration and combinationsthereof attached to the parent structure through an oxygen. Examplesinclude methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy and the like. “Lower alkoxy” refers to alkoxy groupscontaining one to six carbons. In some embodiments, C₁-C₄ alkyl is analkyl group which encompasses both straight and branched chain alkyls offrom 1 to 4 carbon atoms.

“Substituted alkoxy” refers to alkoxy wherein the alkyl constituent issubstituted (i.e., —O-(substituted alkyl)).

Unless stated otherwise specifically in the specification, the alkylmoiety of an alkoxy group is optionally substituted by one or moresubstituents as defined above. Such substituents further independentlyinclude: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —C(O)N(R^(a)), —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),— N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkoxycarbonyl” refers to a group of the formula (alkoxy)(C═O)-attachedthrough the carbonyl carbon wherein the alkoxy group has the indicatednumber of carbon atoms. Thus a C₁-C₆ alkoxycarbonyl group is an alkoxygroup having from 1 to 6 carbon atoms attached through its oxygen to acarbonyl linker. “Lower alkoxycarbonyl” refers to an alkoxycarbonylgroup wherein the alkoxy group is a lower alkoxy group. In someembodiments, C₁-C₄ alkoxy, is an alkoxy group which encompasses bothstraight and branched chain alkoxy groups of from 1 to 4 carbon atoms.

“Substituted alkoxycarbonyl” refers to the group (substitutedalkyl)-O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality.

Unless stated otherwise specifically in the specification, the alkylmoiety of an alkoxycarbonyl group is optionally substituted by one ormore substituents as defined above. Such substituents furtherindependently include: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), SR^(a), —OC(O)—R^(a). —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R)₂, —(R^(a))C(O)OR^(a), —N(R)C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)OR^(a) (where t is 1 or2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, where eachR^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Acyl” refers to the groups (alkyl)-C(O)—, (aryl)-C(O)—,(heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and (heterocycloalkyl)-C(O)—,wherein the group is attached to the parent structure through thecarbonyl functionality. In some embodiments, it is a C₁-C₁₀ acyl radicalwhich refers to the total number of chain or ring atoms of the alkyl,aryl, heteroaryl or heterocycloalkyl portion of the acyloxy group plusthe carbonyl carbon of acyl, i.e. three other ring or chain atoms pluscarbonyl. If the R radical is heteroaryl or heterocycloalkyl, the heteroring or chain atoms contribute to the total number of chain or ringatoms.

Unless stated otherwise specifically in the specification, the “R” of anacyloxy group is optionally substituted by one or more substituents asdefined above. Such substituents further independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl —OR^(a),SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R)₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl. “Acyloxy” refers to a R(C═O)O— radicalwherein “R” is alkyl, aryl, heteroaryl, heteroalkyl, orheterocycloalkyl, which are as described herein. In some embodiments, itis a C₁-C₄ acyloxy radical which refers to the total number of chain orring atoms of the alkyl, aryl, heteroaryl or heterocycloalkyl portion ofthe acyloxy group plus the carbonyl carbon of acyl, i.e. three otherring or chain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms.

Unless stated otherwise specifically in the specification, the “R” of anacyloxy group is optionally substituted by one or more substituents asdefined above. Such substituents further independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a).—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Amino” or “amine” refers to a —N(R^(a))₂ radical group, where eachR^(a) is independently hydrogen alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl, unless stated otherwise specifically inthe specification. When a —N(R^(a))₂ group has two R^(a) other thanhydrogen they can be combined with the nitrogen atom to form a 4-, 5-,6-, or 7-membered ring. For example, —N(R^(a))₂ is meant to include, butnot be limited to, 1-pyrrolidinyl and 4-morpholinyl.

Unless stated otherwise specifically in the specification, an aminogroup is optionally substituted by one or more substituents as definedabove. Such substituents further independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R²)₂, —C(O)R^(a), —C(O)OR^(a), OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR, —N(R)C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl andeach of these moieties may be optionally substituted as defined herein.

“Substituted amino” also refers to N-oxides of the groups —NHR^(d), andNR^(d)R^(d) each as described above. N-oxides can be prepared bytreatment of the corresponding amino group with, for example, hydrogenperoxide or m-chloroperoxybenzoic acid. The person skilled in the art isfamiliar with reaction conditions for carrying out the N-oxidation.

An “ammonium” ion includes the unsubstituted ammonium ion NH₄ ⁺, butunless otherwise specified, it also includes any protonated orquaternarized forms of amines. Thus, trimethylammonium hydrochloride andtetramethylammonium chloride are both ammonium ions, and amines, withinthe meaning herein.

“Amide” or “amido” refers to a chemical moiety with formula —C(O)N(R)₂or —NHC(O)R, where R is selected from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), each of which moiety mayitself be optionally substituted. In some embodiments it is a C₁-C₄amido or amide radical, which includes the amide carbonyl in the totalnumber of carbons in the radical. The R₂ of —N(R)₂ of the amide mayoptionally be taken together with the nitrogen to which it is attachedto form a 4-, 5-, 6-, or 7-membered ring. Unless stated otherwisespecifically in the specification, an amido group is optionallysubstituted independently by one or more of the substituents asdescribed herein for alkyl, cycloalkyl, aryl, heteroaryl, orheterocycloalkyl. An amide may be an amino acid or a peptide moleculeattached to a compound of Formula (I), thereby forming a prodrug. Anyamine, hydroxy, or carboxyl side chain on the compounds described hereincan be amidified. The procedures and specific groups to make such amidesare known to those of skill in the art and can readily be found inreference sources such as Greene and Wuts, Protective Groups in OrganicSynthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which isincorporated herein by reference in its entirety.

“Aryl” refers to a conjugated pi radical with six or ten ring atomswhich has at least one ring having a conjugated pi electron system whichis carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Bivalentradicals formed from substituted benzene derivatives and having the freevalences at ring atoms are named as substituted phenylene radicals.Bivalent radicals derived from univalent polycyclic hydrocarbon radicalswhose names end in “-yl” by removal of one hydrogen atom from the carbonatom with the free valence are named by adding “-idene” to the name ofthe corresponding univalent radical, e.g., a naphthyl group with twopoints of attachment is termed naphthylidene. The term includesmonocyclic or fused-ring polycyclic (i.e., rings which share adjacentpairs of ring atoms) groups.

Unless stated otherwise specifically in the specification, an arylmoiety is optionally substituted by one or more substituents as definedabove. Such substituents further are independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively.

“Ester” refers to a chemical radical of formula —COOR, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). Any amine, hydroxy, or carboxyl side chain onthe compounds described herein can be esterified. The procedures andspecific groups to make such esters are known to those of skill in theart and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York. N.Y., 1999, which is incorporated herein by reference inits entirety.

Unless stated otherwise specifically in the specification, an estergroup is optionally substituted by one or more substituents as definedabove. Such substituents further independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl. —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂.—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical may be optionally substituted as defined above foran alkyl group.

“Functional substituent, group or component” refers to a substituentcapable of displaying functionality such as and including hydroxyl,ester, amide, amine, enamine, halogen, cyano, thio, oxidized sulfur,nitrogen or phosphorus groups, alkoxy, olefinic, aldehyde, ketone,carboxylic acid, anhydride, urethane, urea, imine, amidine,hydroxylimine, hydroxylamine, nitrile, organometallic, and any othergroup capable of displaying dipole interaction and/or reactivity. SeeBasic Principles of Organic Chemistry. Roberts & Casario, W. A.Benjamin, publisher New York, N.Y. 1965, Chapter 10. Additional examplesinclude hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), C(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R)₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2). —S(O)_(t)N(R^(a))₂ (where t is 1 or2), —R^(a)—N(R^(a))₂ or PO₃(R^(a))₂ where each R^(a) is independentlyhydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl orany combination thereof.

“Halo”, “halide”, or, alternatively. “halogen” means fluoro, chloro,bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and“haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine.

“Heteroalkyl” “heteroalkenyl” and “heteroalkynyl” include optionallysubstituted alkyl, alkenyl and alkynyl radicals and which have one ormore skeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range may be given, e.g. C₁-C₄ heteroalkyl which refers to thechain length in total, which in this example is 4 atoms long. Forexample, a —CH₂OCH₂CH₃ radical is referred to as a “C₄” heteroalkyl,which includes the heteroatom center in the atom chain lengthdescription. Connection to the rest of the molecule may be througheither a heteroatom or a carbon in the heteroalkyl chain.

A heteroalkyl group may be substituted with one or more substituents asdefined above. Such substituents further independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro,oxo, thioxo, trimethylsilanyl, —OR^(a), —SR, —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R)₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2).—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical whereheteroalkyl and aryl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and aryl respectively.

“Heteroalkylheteroaryl” refers to an -(heteroalkyl)heteroaryl radicalwhere heteroalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and heteroaryl respectively.

“Heteroalkylheterocycloalkyl” refers to an-(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heteroarylare as disclosed herein and which are optionally substituted by one ormore of the substituents described as suitable substituents forheteroalkyl and heterocycloalkyl respectively.

“Heteroalkylcycloalkyl” refers to an -(heteroalkyl) cycloalkyl radicalwhere heteroalkyl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and cycloalkyl respectively.

“Heteroaryl” refers to a 5, 6 or 10-membered aromatic radical (e.g.,C₅-C₁₃ heteroaryl) that includes one or more ring heteroatoms selectedfrom nitrogen, oxygen and sulfur, and which may be a monocyclic,bicyclic, tricyclic or tetracyclic ring system. Whenever it appearsherein, a numerical range refers to each integer in the given range. AnN-containing “heteroaromatic” or “heteroaryl” moiety refers to anaromatic group in which at least one of the skeletal atoms of the ringis a nitrogen atom. The polycyclic heteroaryl group may be fused ornon-fused. The heteroatom(s) in the heteroaryl radical is optionallyoxidized. One or more nitrogen atoms, if present, are optionallyquaternized. The heteroaryl is attached to the rest of the moleculethrough any atom of the ring(s). Examples of heteroaryls include, butare not limited to adcninyl, azabenzimidazolyl, azaindolyl, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,imnidazopyridinyl, isoxazolopyridinyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thianaphthalenyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl,thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl), xanthinyl,guaninyl, quinoxalinyl, and quinazolinyl groups.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracen yl, 2-anthracen yl, 3-anthracenyl), thiophen yl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl,acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl),imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimindinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyrazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1l-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,1-dihydro-5H-dibenz[h,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Unless stated otherwise specifically in the specification, a heterarylmoiety is optionally substituted by one or more substituents as definedabove. Such substituents further independently include: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro,oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR, —C(O)N(R^(a))₂, —N(R)C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R)₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O—) substituents, such as pyridinyl N-oxides.

“Heterocyclyl” refers to any monocyclic or polycyclic moiety comprisingat least one heteroatom selected from nitrogen, oxygen and sulfur. Asused herein, heterocyclyl moieties can be aromatic or nonaromatic.

Unless stated otherwise, heterocyclyl moieties are optionallysubstituted by one or more substituents as defined above. Suchsubstituents further independently include: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2). —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl or heteroarylalkyl.

“Heteroarylalkyl” refers to a moiety having an aryl moiety, as describedherein, connected to an alkylene moiety, as described herein, whereinthe connection to the remainder of the molecule is through the alkylenegroup.

“Heterocyclylalkyl” refers to a stable 5, 6 or 10-membered non-aromaticring radical having from one to six heteroatoms selected from nitrogen,oxygen and sulfur. Unless stated otherwise specifically in thespecification, the heterocycloalkyl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems. The heteroatoms in the heterocycloalkyl radical may beoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heterocycloalkyl radical is partially orfully saturated. The heterocycloalkyl may be attached to the rest of themolecule through any atom of the ring(s). Examples of suchheterocycloalkyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl.

Unless stated otherwise specifically in the specification, aheterocycloalkyl moiety is optionally substituted by one or moresubstituents as defined above. Such substituents further independentlyinclude: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂(where t is 1 or 2), or PO₃(R^(a))₂, where each R^(a) is independentlyhydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

“Heterocyclylalkyl” also includes bicyclic ring systems wherein onenon-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2carbon atoms in addition to 1-3 heteroatoms independently selected fromoxygen, sulfur, and nitrogen, as well as combinations comprising atleast one of the foregoing heteroatoms; and the other ring, usually with3 to 7 ring atoms, optionally contains 1-3 heteroatoms independentlyselected from oxygen, sulfur, and nitrogen and is not aromatic.

The term “(C_(x)-C_(y))perfluoroalkyl,” wherein x<y, means an alkylgroup with a minimum of x carbon atoms and a maximum of y carbon atoms,wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is—(C₁-C₆)perfluoroalkyl, more preferred is —(C₁-C₃)perfluoroalkyl, mostpreferred is —CF₃.

The term “(C_(x)-C_(y))perfluoroalkylene,” wherein x<y, means an alkylgroup with a minimum of x carbon atoms and a maximum of y carbon atoms,wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is—(C₁-C₆)perfluoroalkylene, more preferred is —(C₁-C₃)perfluoroalkylene,most preferred is —CF₂—.

“Sulfanyl” refers to the groups: —S-(optionally substituted alkyl),—S-(optionally substituted aryl), —S-(optionally substitutedheteroaryl), and —S-(optionally substituted heterocycloalkyl).

“Sulfinyl” refers to the groups: —S(O)—H, —S(O)-(optionally substitutedalkyl), —S(O)-(optionally substituted amino). —S(O)-(optionallysubstituted aryl), —S(O)-(optionally substituted heteroaryl), and—S(O)-(optionally substituted heterocycloalkyl).

“Sulfonyl” refers to the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted alkyl), —S(O₂)-(optionally substituted amino).—S(O₂)-(optionally substituted aryl), —S(O₂)-(optionally substitutedheteroaryl), and —S(O₂)-(optionally substituted heterocycloalkyl).

“Sulfonamidyl” or “sulfonamido” refers to a —S(═O)₂—NRR radical, whereeach R is selected independently from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon). The R groups in —NRR ofthe —S(═O)₂—NRR radical may be taken together with the nitrogen to whichit is attached to form a 4-, 5-, 6-, or 7-membered ring. In someembodiments, it is a C₁-C₁₀ sulfonamido, wherein each R in sulfonamidocontains 1 carbon, 2 carbons, 3 carbons, or 4 carbons total. Asulfonamido group is optionally substituted by one or more of thesubstituents described for alkyl, cycloalkyl, aryl, heteroarylrespectively.

“Sulfoxyl” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon). Asulfonate group is optionally substituted on R by one or more of thesubstituents described for alkyl, cycloalkyl, aryl, heteroarylrespectively.

“Azido” refers to an N₃ group. An “azide” can be an organic azide or canbe a salt of the azide (N₃₎ anion. The term “nitro” refers to an NO₂group bonded to an organic moiety. The term “nitroso” refers to an NOgroup bonded to an organic moiety. The term nitrate refers to an ONO₂group bonded to an organic moiety or to a salt of the nitrate (NO₃ ⁻)anion.

“Urethane” (“carbamoyl” or “carbamyl”) includes N- and O-urethanegroups, i.e., —NRC(O)OR and —OC(O)NR₂ groups, respectively.

“Sulfonamide” (or “sulfonamido”) includes S- and N-sulfonamide groups,i.e., —SO₂NR₂ and —NRSO₂R groups, respectively. Sulfonamide groupstherefore include but are not limited to sulfamoyl groups (—SO₂NH₂). Anorganosulfur structure represented by the formula —S(O)(NR)— isunderstood to refer to a sulfoximine, wherein both the oxygen and thenitrogen atoms are bonded to the sulfur atom, which is also bonded totwo carbon atoms.

“Amidine” or “amidino” includes groups of the formula —C(NR)NR₂.Typically, an amidino group is —C(NH)NH₂.

“Guanidine” or “guanidino” includes groups of the formula —NRC(NR)NR₂.Typically, a guanidino group is —NHC(NH)NH₂.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compounds of thepresent invention may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds of theinvention. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility inprocess of synthesis, purification or formulation of compounds of theinvention.

Suitable pharmaceutically acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid. Examples ofpharmaceutically unacceptable acid addition salts include, for example,perchlorates and tetrafluoroborates. Representative salts include thehydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate,acetate, valerate, oleate, palmitate, stearate, laurate, benzoate,lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,tartrate, naphthylate, mesylate, glucoheptonate, lactobionate,laurylsulphonate salts, and amino acid salts, and the like. (See, forexample, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.)

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. Although pharmaceutically unacceptable salts are notgenerally useful as medicaments, such salts may be useful, for exampleas intermediates in the synthesis of Formula (I) compounds, for examplein their purification by recrystallization. All of these salts may beprepared by conventional means from the corresponding compound accordingto Formula (I) by reacting, for example, the appropriate acid or basewith the compound according to Formula (I). The term “pharmaceuticallyacceptable salts” refers to nontoxic inorganic or organic acid and/orbase addition salts, see, for example, Lit et al., Salt Selection forBasic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated byreference herein.

A “hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometricquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form, i.e., a compound in water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “solvate” is a similar composition except that a solvent other thatwater replaces the water. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometric or non-stoichiometric.As the term is used herein a “solvate” refers to a solid form, i.e., acompound in solution in a solvent, while it may be solvated, is not asolvate as the term is used herein.

A “prodrug” as is well known in the art is a substance that can beadministered to a patient where the substance is converted in vivo bythe action of biochemicals within the patient's body, such as enzymes,to the active pharmaceutical ingredient. Examples of prodrugs includeesters of carboxylic acid groups, which can be hydrolyzed by endogenousesterases as are found in the bloodstream of humans and other mammals.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. II. Bundgaard, Elsevier, 1985.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described. Moreover, where features or aspects ofthe invention are described in terms of Markush groups, those skilled inthe art will recognize that the invention is also thereby described interms of any combination of individual members or subgroups of membersof Markush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

If a value of a variable that is necessarily an integer, e.g., thenumber of carbon atoms in an alkyl group or the number of substituentson a ring, is described as a range, e.g., 0-4, what is meant is that thevalue can be any integer between 0 and 4 inclusive, i.e., 0, 1, 2, 3, or4.

In various embodiments, the compound or set of compounds, such as areused in the inventive methods, can be any one of any of the combinationsand/or sub-combinations of the above-listed embodiments.

In various embodiments, a compound as shown in any of the Examples, oramong the exemplary compounds, is provided. Provisos may apply to any ofthe disclosed categories or embodiments wherein any one or more of theother above disclosed embodiments or species may be excluded from suchcategories or embodiments.

The term “amino protecting group” or “N-protected” as used herein refersto those groups intended to protect an amino group against undesirablereactions during synthetic procedures and which can later be removed toreveal the amine.

Commonly used amino protecting groups are disclosed in Protective Groupsin Organic Synthesis. Greene, T. W.; Wuts, P. G. M., John Wiley & Sons,New York, N.Y. (3rd Edition, 1999). Amino protecting groups include acylgroups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- oraryloxy-carbonyl groups (which form urethanes with the protected amine)such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl,isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl(Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl(Teoc), phenoxycarbonyl 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like; and silyl groups such as trimethylsilyl and the like.Amine protecting groups also include cyclic amino protecting groups suchas phthaloyl and dithiosuccinimidyl, which incorporate the aminonitrogen into a heterocycle. Typically, amino protecting groups includeformyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc,Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of theordinary artisan to select and use the appropriate amino protectinggroup for the synthetic task at hand.

The term “hydroxyl protecting group” or “O-protected” as used hereinrefers to those groups intended to protect an OH group againstundesirable reactions during synthetic procedures and which can later beremoved to reveal the amine. Commonly used hydroxyl protecting groupsare disclosed in Protective Groups in Organic Synthesis, Greene, T. W.;Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3nd Edition, 1999).Hydroxyl protecting groups include acyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, α-chlorobutyryl,benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like;acyloxy groups (which form urethanes with the protected amine) such asbenzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl,isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl(Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl(Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like; and silyl groups such as trimethylsilyl and the like. Itis well within the skill of the ordinary artisan to select and use theappropriate hydroxyl protecting group for the synthetic task at hand.

At various places in the present specification substituents of compoundsof the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C1-C6 alkyl” is specifically intended to individuallydisclose methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl,etc. For a number qualified by the term “about”, a variance of 2%, 5%,10% or even 20% is within the ambit of the qualified number.

Standard abbreviations for chemical groups such as are well known in theart are used: e.g., Me=methyl, Et=ethyl, i-Pr=isopropyl. Bu=butyl,t-Bu=tert-butyl, Ph=phenyl, Bn=benzyl, Ac=acetyl, Bz=benzoyl, and thelike.

Compounds

The invention is directed to fused pyrimidine compounds that inhibitATPase Associated with a variety of Activities (AAA), the ATPase havingthe descriptive name Valosin containing protein, also known as p97, aswell as methods to treat or prevent a disease or condition in a subjectthat would benefit by inhibition of p97. The compounds embodying thefirst aspect of the invention are fused cyclohexyl-pyrimidines,cyclopentyl-pyrimidines and cycloheptyl-pyrimidines having an allcarbon, aza, oxa or thia ring as the cyclopentyl, cyclohexyl orcycloheptyl fusion partner of the fused pyrimidine.

The fused pyrimidines have a benzyl amino group or substituted benzylamino group at the 4 position of the fused pyrimidine or pyrimidine ringand a Het group at the 2 position. The Het group is as defined above.Formula I provides a pictorial-structural understanding of the foregoingdescription of embodiments of the fused pyrimidine compounds of theinvention.

The substituents R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ of Formula I are eachindependently selected from the group consisting of hydrogen, anoptionally substituted aliphatic group, an optionally substitutedaromatic group and an optionally substituted functional group asdescribed above in the definitions section.

Preferred designations for A, D, E, B and Z for the fused pyrimidinecompounds of Formula I independently and separately are those in which Ais N or A is C.

Preferred designations for A, D, E, B and Z for the fused pyrimidinecompounds of Formula I independently and separately are those in which Dand E are both C and those in which one of D and E is N.

Preferred designations for A, D, E, B and Z for the fused pyrimidinecompounds of Formula I independently and separately are those in which Ais N and D and E are both C.

Preferred designations for A, D, E, B and Z for the fused pyrimidinecompounds of Formula I independently and separately are those in whichA, D and E are all C.

Preferred designations for A, D, E, B and Z for the fused pyrimidinecompounds of Formula I independently and separately are those in which Aand D are both C and B and E are both N.

Preferred designations for A, D, E, B and Z for the fused pyrimidinecompounds of Formula I independently and separately are those in which Ais C, one of D and E is N and the other is C, and Z and B are eachindependently N or CR⁶.

A preferred designation for R³ for the fused pyrimidine compounds ofFormula I and for any of the foregoing preferred designations of A, B,D, E and Z is hydrogen or unsubstituted or substituted 1-4 carbon alkyl.

A preferred designation for Y for the fused pyrimidine compounds ofFormula I and for any of the foregoing preferred designations of A, B,D, E and Z is NR⁵ and R⁵ is hydrogen or unsubstituted or substituted 1-4carbon alkyl.

A preferred designation for Y for the fused pyrimidine compounds ofFormula I and for any of the foregoing preferred designations of A, B,D, E and Z is O.

A preferred designation for Y for the fused pyrimidine compounds ofFormula I and for any of the foregoing preferred designations of A, B,D, E and Z is S.

A preferred designation for Y for the fused pyrimidine compounds ofFormula I and for any of the foregoing preferred designations of A, B,D, E and Z is CR⁴.

Preferably, the substituents R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ of Formula Ieach are independently selected from the group consisting of hydrogen,halogen, alkyl, CN, OR′, CN, SR′, SO₂R′, NR′R″, C(O)R′, C(O)NR′R″,C(O)OR′, OC(O)R′, OC(O) NR′R″, N(R′)C(O)OR′, N(R′)C(O)R″,N(R′)C(O)N(R″R), N(R′)C(NR′)N(RR³), N(R^(a))S(O)₂R″, S(O)₂OR′,S(O)₂N(R′R″), N(R^(d))₂, (CR′R″)^(t) N(RR³), (CR′R″)^(t)OR, PO₃(R′R″),CF wherein each R, R³, R′ and R″ each are independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl alkenyl, alkynyl or anycombination thereof; and wherein and each t is independently selectedfrom the group of integers of 1 and 2.

More preferably, the substituents R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ ofFormula I are each independently selected from hydrogen, halogen,linear, branched or cyclo alkyl of 1 to 6 carbons, carboxyl,carboxamide, substituted amino methyl, sulfonyl, sulfonamide, amine,mono, di or trialkyl amine of 1 to 6 carbons, nitrile, halogen, N-alkylcarboxamide of 1 to 6 carbons in the alkyl group, perfluoroalkyl of 1 to3 carbons, alkoxy of 1 to 6 carbons.

Especially preferably for Formula I, R^(L) is substituted at the 4position of the Het group. Also, especially preferably, the R² group ishydrogen. Also preferably, the fused pyrimidine compounds of Formula Imay substituted with R³ which may be selected from alkyl of 1 to 3carbons, perfluoroalkyl of 1 to 3 carbons, alkoxy of 1 to 3 carbons,alkylsulfone of 1 to 3 carbons, aminomethyl (—NHCH₃), methylamine(—CH₂NH₂), methanol (—CH₂OH), nitrile or halogen. These substituents R¹,R² and R³ of the fused pyrimidine compounds of Formula I can alsopreferably be hydrogen. Especially more preferably, these substituentsR¹, R² and R³ of Formula I are each independently hydrogen, methyl,trifluoromethyl, methoxy or chloro.

The group R¹ is a substituent of the benzo moiety of the IIET group mayespecially preferably be:

1. carboxylic acid —CO₂H

2. carboxamide —CONH₂

3. methyl amine —CH₂NH₂

4. methyl alcohol —CH₂OH

5. acetic acid —CH₂CO₂H

6. acetamide —CH₂CONH₂

7. methyl acetamide —CH₂NHCOCH₂

8. methyl propanamide —CH₂NHCOCH₂CH₃

9. methyl-2-methylpropanamide —CH₂NHCOCH(CH₃)CH₃

10. methyl methanesulfonamide —CH₂NHSO₂CH₃

11. methyl ethanesulfonamide —CH₂NHSO₂CH₂CH₃

12. methyl-2-methylethanesulfonamide —CH₂NHSO₂CH(CH₃)CH₃

13. methyl propanesulfonamide —CH₂NHSO₂CH₂CH₂CH₃

14. methyl-1-methylpropanesulfonamide —CH₂NHSO₂CH(CH₃)CH₂CH₃

15. methyl-2-methylpropanesulfonamide —CH₂NHSO₂CH₂CH(CH₃)CH₃

The group R² is an optional substituent of the benzo moiety of the HETgroup and especially preferably may be hydrogen, alkyl of 1 to 3carbons, nitrile, perfluoroalkyl of 1 to 3 carbons.

Embodiments of the scaffold (Formula II) and the HET moiety (FormulaHET) include the following structures. In each of these embodiments andthe preferred, more preferred, especially more preferred and mostpreferred combinations, the substituent groups R¹, R², R³, R⁴, R⁵, R⁶and R⁷ are included as provided by Formula I. For each of theseembodiments and the preferred, more preferred, especially more preferredand most preferred combinations of Formula II and Formula IIET formingpreferences for Formula I, the preferred and more preferred designationsgiven above for substituent groups R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ as wellas the especially preferred designations for substituent groups R¹, R²and R³ are preferences applied to these preferred combinations as well.

Embodiments of Formula II, the Scaffold (labeled as S for scaffold) are:

Preferred scaffold embodiments include S2, S3, S4, and S5 when the HETembodiments depicted below include any of the structures except H5 andH10. Especially preferred scaffold embodiments include S1, S3, S6 and S7in combination with any of the HET embodiments depicted below.

Embodiments of Formula IIET (labeled II for heterocyclic) whereinN-indicates the nitrogen of the group NR⁷ are:

Especially preferred combinations of the scaffold and HET embodimentsforming preferred embodiments of Formula I include each of S1, S2, S3,S4, S5, S6 and S7 bound with any one of H4, H5, H6, H7, H8, H9, H10,H11, H12, H13, H14, H17 and H22. According to the provisos set forthabove for Formula I, H15 and H10 are not combined with S2, S4 and S5. Asstated above, the substituent groups R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ areincluded as provided by Formula I. The preferred and more preferreddesignations given above for substituent groups R¹, R², R³, R⁴, R⁵, R⁶and R⁷ as well as the especially preferred designations for substituentgroups R¹, R² and R³ are preferences for these substituent groups asapplied to the foregoing combinations of scaffold and HET embodimentsfor Formula I.

Especially preferred combinations of the scaffold and HET embodimentsforming especially preferred embodiments of Formula I include each ofS1, S2, S3, S4, S5, S6 and S7 bound with any one of H4, H5, H6, H7, H9,H10, H13 and H17. According to the provisos set forth above for FormulaI, H5 and H10 are not combined with S2, S4 and S5. As stated above, thesubstituent groups R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are included asprovided by Formula I. The preferred and more preferred designationsgiven above for substituent groups R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ as wellas the especially preferred designations for substituent groups R¹, R²and R³ are preferences for these substituent groups as applied to theforegoing combinations of scaffold and HET embodiments for Formula I.

Most preferred combinations of the scaffold embodiment and the HETembodiment forming most preferred embodiments of Formula I are chosenfrom S2, S4, S5, S9, S10 and S11 combined with H4. As stated above, thiscombination includes the substituents R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ asdisclosed in Formula I. The preferred and more preferred designationsgiven above for substituent groups R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ as wellas the especially preferred designations for substituent groups R¹, R²and R³ are preferences for these substituent groups as applied to theforegoing combinations of scaffold and HET embodiments for Formula I.

Most especially preferred combinations of the scaffold embodiment andthe HET embodiment are chosen from S2, S4, S5, S9, S10 and S11 combinedwith H6, H7, H8, H9, H13, H17 and H22. As stated above, this combinationincludes the substituents R¹, R², R³, R⁴, R⁵⁵, R⁶ and R⁷ as disclosed inFormula I.

The preferred and more preferred designations given above forsubstituent groups R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ as well as theespecially preferred designations for substituent groups R¹, R² and R³are preferences for these substituent groups as applied to the foregoingcombinations of scaffold and IIET embodiments for Formula I.

Mechanism of Action and Medical Treatment

In certain embodiments, the invention is directed to methods ofinhibiting p97. The fused pyrimidine compounds of the invention for usein the methods disclosed herein bind to the active site of p97, e.g.,noncovalently or covalently.

In certain such embodiments, the covalent binding may be reversible orirreversible.

The compounds of the invention and their pharmaceutical compositions arecapable of acting as “inhibitors” of p97 which means that they arecapable of blocking or reducing the activity of an enzyme, for example,inhibition of various activities of p97. An inhibitor can act withcompetitive, uncompetitive, or noncompetitive inhibition. An inhibitorcan bind reversibly or irreversibly, and therefore the term includescompounds that are suicide the enzyme, or it can cause a conformationalchange elsewhere on the enzyme.

The compounds of the invention and their pharmaceutical compositionsfunction as therapeutic agents in that they are capable of preventing,ameliorating, modifying and/or affecting a disorder or condition refersto a compound that, in a statistical sample, reduces the occurrence ofthe disorder or condition in the treated sample relative to an untreatedcontrol sample, or delays the onset or reduces the severity of one ormore symptoms of the disorder or condition relative to the untreatedcontrol sample.

The ability to prevent, ameliorate, modify and/or affect in relation toa condition, such as a local recurrence (e.g., pain), a disease such ascancer, a syndrome complex such as heart failure or any other medicalcondition, is well understood in the art, and includes administration ofa composition which reduces the frequency of, or delays the onset of,symptoms of a medical condition in a subject relative to a subject whichdoes not receive the composition. Thus, prevention of cancer includes,for example, reducing the number of detectable cancerous growthspopulation, and/or delaying the appearance of detectable cancerousgrowths in a treated population versus an untreated control population,e.g., by a statistically and/or clinically significant amount.

Prevention of an infection includes, for example, reducing the number ofdiagnoses of the infection in a treated population versus an untreatedcontrol population, and/or delaying the onset of symptoms of theinfection in a treated population versus an untreated controlpopulation. Prevention of pain includes, for example, reducing themagnitude of, or alternatively delaying, pain sensations experienced bysubjects in a treated population versus an untreated control population.

The compounds of the invention and their pharmaceutical compositions arecapable of functioning prophylacticly and/or therapeutically and includeadministration to the host of one or more of the subject compositions.If it is administered prior to clinical manifestation of the unwantedcondition (e.g., disease or other unwanted state of the host animal)then the treatment is prophylactic, (i.e., it protects the host againstdeveloping the unwanted condition), whereas if it is administered aftermanifestation of the unwanted condition, the treatment is therapeutic,(i.e., it is intended to diminish, ameliorate, or stabilize the existingunwanted condition or side effects thereof).

The compounds of the invention and their pharmaceutical compositions arecapable of prophylactic and/or therapeutic treatments. If a compound orpharmaceutical composition is administered prior to clinicalmanifestation of the unwanted condition (e.g., disease or other unwantedstate of the host animal) then the treatment is prophylactic, (i.e., itprotects the host against developing the unwanted condition), whereas ifit is administered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).As used herein, the term “treating” or “treatment” includes reversing,reducing, or arresting the symptoms, clinical signs, and underlyingpathology of a condition in manner to improve or stabilize a subject'scondition.

The compounds of the invention and their pharmaceutical compositions canbe administered in “therapeutically effective amounts” with respect tothe subject method of treatment. The therapeutically effective amount isan amount of the compound(s) in a pharmaceutical composition which, whenadministered as part of a desired dosage regimen (to a mammal,preferably a human) alleviates a symptom, ameliorates a condition, orslows the onset of disease conditions according to clinically acceptablestandards for the disorder or condition to be treated or the cosmeticpurpose, e.g., at a reasonable benefit/risk ratio applicable to anymedical treatment.

Administration

Compounds of the invention and their pharmaceutical compositionsprepared as described herein can be administered in various forms,depending on the disorder to be treated and the age, condition, and bodyweight of the patient, as is well known in the art. As is consistent,recommended and required by medical authorities and the governmentalregistration authority for pharmaceuticals, administration is ultimatelyprovided under the guidance and prescription of an attending physicianwhose wisdom, experience and knowledge control patient treatment.

For example, where the compounds are to be administered orally, they maybe formulated as tablets, capsules, granules, powders, or syrups; or forparenteral administration, they may be formulated as injections(intravenous, intramuscular, or subcutaneous), drop infusionpreparations, or suppositories. For application by the ophthalmic mucousmembrane route or other similar transmucosal route, they may beformulated as drops or ointments.

These formulations for administration orally or by a transmucosal routecan be prepared by conventional means, and if desired, the activeingredient may be mixed with any conventional additive or excipient,such as a binder, a disintegrating agent, a lubricant, a corrigent, asolubilizing agent, a suspension aid, an emulsifying agent, a coatingagent, a cyclodextrin, and/or a buffer. Although the dosage will varydepending on the symptoms, age and body weight of the patient, thegender of the patient, the nature and severity of the disorder to betreated or prevented, the route of administration and the form of thedrug, in general, a daily dosage of from 0.0001 to 2000 mg, preferably0.001 to 1000 mg, more preferably 0.001 to 500 mg, especially morepreferably 0.001 to 250 mg, most preferably 0.001 to 150 mg of thecompound is recommended for an adult human patient, and this may beadministered in a single dose or in divided doses. Alternatively, adaily dose can be given according to body weight such as 1 nanogram/kg(ng/kg) to 200 mg/kg, preferably 10 ng/kg to 100 mg/kg, more preferably10 ng/kg to 10 mg/kg, most preferably 10 ng/kg to 1 mg/kg. The amount ofactive ingredient which can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect.

The precise time of administration and/or amount of the composition thatwill yield the most effective results in terms of efficacy of treatmentin a given patient will depend upon the activity, pharmacokinetics, andbioavailability of a particular compound, physiological condition of thepatient (including age, sex, disease type and stage, general physicalcondition, responsiveness to a given dosage, and type of medication),route of administration, etc. However, the above guidelines can be usedas the basis for fine-tuning the treatment, e.g., determining theoptimum time and/or amount of administration, which will require no morethan routine experimentation consisting of monitoring the subject andadjusting the dosage and/or timing.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose ligands, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Pharmaceutical Compositions Incorporating Formula I

The pharmaceutical compositions of the invention incorporate embodimentsof a fused pyrimidine compound of Formula I of the invention and apharmaceutically acceptable carrier. The nature of the pharmaceuticalcarrier and the dose of the fused pyrimidine compound of Formula Idepend upon the route of administration chosen, the effective dose forsuch a route and the wisdom and experience of the attending physician.

A “pharmaceutically acceptable carrier” is a pharmaceutically acceptablematerial, composition, or vehicle, such as a liquid or solid filler,diluent, excipient, solvent or encapsulating material. Each carrier mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not injurious to the patient. Someexamples of materials which can serve as pharmaceutically acceptablecarriers include: (1) sugars, such as lactose, glucose, and sucrose; (2)starches, such as corn starch, potato starch, and substituted orunsubstituted β-cyclodextrin; (3) cellulose, and its derivatives, suchas sodium carboxymethyl cellulose, ethyl cellulose, and celluloseacetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)excipients, such as cocoa butter and suppository waxes; (9) oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11)polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol;(12) esters, such as ethyl oleate and ethyl laurate; (13) agar, (14)buffering agents, such as magnesium hydroxide and aluminum hydroxide;(15) alginic acid; (16) pyrogen free water; (17) isotonic saline; (18)Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions;and (21) other non-toxic compatible substances employed inpharmaceutical formulations.

Wetting agents, emulsifiers, and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring, and perfuming agents,preservatives and antioxidants can also be present in the compositions.Examples of pharmaceutically acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like;(2) oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations suitable for oral administration may be in the form ofcapsules, cachets, pills, tablets, lozenges (using a flavored basis,usually sucrose and acacia or tragacanth), powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert matrix, such as gelatin and glycerin, orsucrose and acacia) and/or as mouthwashes, and the like, each containinga predetermined amount of a compound of the invention as an activeingredient. A composition may also be administered as a bolus,electuary, or paste.

In solid dosage form for oral administration (capsules, tablets, pills,dragees, powders, granules, and the like), a compound of the inventionis mixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following:

-   -   (1) fillers or extenders, such as starches, cyclodextrins,        lactose, sucrose, glucose, mannitol, and/or silicic acid;    -   (2) binders, such as, for example, carboxymethylcellulose,        alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or        acacia;    -   (3) humectants, such as glycerol;    -   (4) disintegrating agents, such as agar-agar, calcium carbonate,        potato or tapioca starch, alginic acid, certain silicates, and        sodium carbonate;    -   (5) solution retarding agents, such as paraffin;    -   (6) absorption accelerators, such as quaternary ammonium        compounds;    -   (7) wetting agents, such as, for example, acetyl alcohol and        glycerol monostearate; (8) absorbents, such as kaolin and        bentonite clay;    -   (9) lubricants, such a talc, calcium stearate, magnesium        stearate, solid polyethylene glycols, sodium lauryl sulfate, and        mixtures thereof; and    -   (10) coloring agents. In the case of capsules, tablets, and        pills, the pharmaceutical compositions may also comprise        buffering agents. Solid compositions of a similar type may also        be employed as fillers in soft and hard-filled gelatin capsules        using such excipients as lactose or milk sugars, as well as high        molecular weight polyethylene glycols, and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered inhibitor(s)moistened with an inert liquid diluent.

Tablets, and other solid dosage forms, such as dragees, capsules, pills,and granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes, and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner.

Examples of embedding compositions which can be used include polymericsubstances and waxes. A compound of the invention can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups,and elixirs. In addition to the active ingredient, the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents, and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn, germ, olive,castor, and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols, and fatty acid esters of sorbitan, and mixturesthereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active inhibitor(s) may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing one or more inhibitor(s)with one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, which is solid at room temperature, butliquid at body temperature and, therefore, will melt in the rectum orvaginal cavity and release the active agent.

Formulations which are suitable for vaginal administration also includepessaries, tampons, creams, gels, pastes, foams, or spray formulationscontaining such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration of aninhibitor(s) include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches, and inhalants. The active componentmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams, and gels may contain, in addition to acompound of the invention, excipients, such as animal and vegetablefats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc, andzinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of theinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates, and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

A compound of the invention can be alternatively administered byaerosol. This is accomplished by preparing an aqueous aerosol, liposomalpreparation, or solid particles containing the composition. A nonaqueous(e.g., fluorocarbon propellant) suspension could be used. Sonicnebulizers are preferred because they minimize exposing the agent toshear, which can result in degradation of the compound.

Ordinarily, an aqueous aerosol is made by formulating an aqueoussolution or suspension of a compound of the invention together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularcomposition, but typically include nonionic surfactants (Tweens,Pluronics, sorbitan esters, lecithin, Cremophors), pharmaceuticallyacceptable co-solvents such as polyethylene glycol, innocuous proteinslike serum albumin, oleic acid, amino acids such as glycine, buffers,salts, sugars, or sugar alcohols. Aerosols generally are prepared fromisotonic solutions.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the invention to the body. Such dosage formscan be made by dissolving or dispersing the agent in the proper medium.Absorption enhancers can also be used to increase the flux of theinhibitor(s) across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing theinhibitor(s) in a polymer matrix or gel.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterile aqueousor nonaqueous solutions, dispersions, suspensions or emulsions, orsterile powders which may be reconstituted into sterile injectablesolutions or dispersions just prior to isotonic with the blood of theintended recipient or suspending or thickening agents. Examples ofsuitable aqueous and nonaqueous carriers which may be employed in thepharmaceutical compositions of the invention include water, ethanol,polyols (such as glycerol propylene glycol, polyethylene glycol and thelike), and suitable mixtures thereof, vegetable oils, such as olive oil,and injectable organic esters, such as ethyl oleate. Proper fluidity canbe maintained, for example, by the use of coating materials, such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include tonicity-adjusting agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a compound of theinvention, it is desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. For example, delayed absorptionof a parenterally administered drug form is accomplished by dissolvingor suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofinhibitor(s) in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

The pharmaceutical compositions may be given orally, parenterally,topically, or rectally. They are, of course, given by forms suitable foreach administration route. For example, they are administered in tabletsor capsule form, by injection, inhalation, eye lotion, ointment,suppository, infusion; topically by lotion or ointment; and rectally bysuppositories. Oral administration is preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtrachal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection, and infusion.

The pharmaceutical compositions of the invention may be “systemicallyadministered” “administered systemically,” “peripherally administered”and “administered peripherally” meaning the administration of a ligand,drug, or other material other than directly into the central nervoussystem, such that it enters the patient's system and thus, is subject tometabolism and other like processes, for example, subcutaneousadministration.

The compound(s) of the invention may be administered to humans and otheranimals for therapy by any suitable route of administration, includingorally, nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally, and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compound(s) ofthe invention, which may be used in a suitable hydrated form, and/or thepharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the compound(s) of the invention in thepharmaceutical compositions of this invention may be varied so as toobtain an amount of the active ingredient which is effective to achievethe desired therapeutic response for a particular patient, composition,and mode of administration, without being toxic to the patient.

The concentration of a compound of the invention in a pharmaceuticallyacceptable mixture will vary depending on several factors, including thedosage of the compound to be administered, the pharmacokineticcharacteristics of the compound(s) employed, and the route ofadministration.

In general, the compositions of this invention may be provided in anaqueous solution containing about 0.1-10% w/v of a compound disclosedherein, among other substances, for parenteral administration. Typicaldose ranges are from about 0.001 to about 50 mg/kg of body weight perday, given in 1-4 divided (loses. Each divided dose may contain the sameor different compounds of the invention. The dosage will be an effectiveamount depending on several factors including the overall health of apatient, and the formulation and route of administration of the selectedcompound(s).

Another aspect of the invention provides a conjoint therapy wherein oneor more other therapeutic agents are administered with the compounds andcompositions of the invention. Such conjoint treatment will achieve thesame or similar treatment accounting for the additive effects of theconjoined therapeutic agents other than the compounds of the invention.

In certain embodiments, a compound of the invention can be conjointlyadministered with one or more proteasome inhibitor(s). In certainembodiments, a compound of the invention is conjointly administered witha chemotherapeutic. Suitable chemotherapeutics may include, naturalproducts such as vinca alkaloids (i.e., vinblastine, vincristine, andvinorelbine), paclitaxe, epidipodophyllotoxins (i.e., etoposide,teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin,doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins,plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase whichsystemically metabolizes L-asparagine and deprives cells which do nothave the capacity to synthesize their own asparagine); antiplateletagents; antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmnelamnines (hexamethylmelamineand thiotepa), alkyl sulfonates (busulfan), nitrosoureas (carmustine(BCNU) and analogs, streptozocin), trazenes—dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, andcytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorxodeoxyadenosine); aromataseinhibitors carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones (i.e., estrogen) and hormone agonists suchas leutinizing hormone releasing hormone (LHRH) agonists (goserelin,leuprolide and triptorelin). Other chemotherapeutic agents may includemechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene,gemcitabine, navelbine, or any analog or derivative variant of theforegoing.

In certain embodiments, a compound of the invention is conjointlyadministered with a steroid. Suitable steroids may include, but are notlimited to, 21-acetoxypregnenolone, alclometasone, algestone,amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone,clobetasol, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,fluclorinide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, hydrocortisone, loteprednoletabonate, paramethasone, prednicarbate, prednisolone, prednisolone25-diethylaminoacetate, prednisolone, sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, triamcinolonehexacetonide, and salts and/or derivatives thereof.

In certain embodiments, a compound of the invention is conjointlyadministered with an immunotherapeutic agent. Suitable immunotherapeuticagents may include, but are not limited to, cyclosporine, thalidomide,and monoclonal antibodies. The monoclonal antibodies can be either nakedor conjugated such as rituximab, tositumomab, alemtuzumab, epratuzumab,ibritumomab tiuxetan, gemtuzamab ozogamicin, bevacizumab, cetuximab,erlotinib and trastuzumab.

Treatment of Cancer

Exemplary forms of cancer which may be treated by the methods of theinvention using the fused pyrimidine compounds of the invention andtheir pharmaceutical compositions include, but are not limited to,prostate cancer, bladder cancer, lung cancer (including either smallcell or non-small cell cancer), colon cancer, kidney cancer, livercancer, breast cancer, cervical cancer, endometrial or other uterinecancer, ovarian cancer, testicular cancer, cancer of the penis, cancerof the vagina, cancer of the urethra, gall bladder cancer, esophagealcancer, or pancreatic cancer.

Additional exemplary forms of cancer which may be treated by the methodsof the invention include, but are not limited to, cancer of skeletal orsmooth muscle, stomach cancer, cancer of the small intestine, cancer ofthe salivary gland, anal cancer, rectal cancer, thyroid cancer,parathyroid cancer, pituitary cancer, and nasopharyngeal cancer.

The compounds of the present invention and their salts and solvates,thereof, may be employed alone or in combination with other therapeuticagents for the treatment of the diseases or conditions associated withinappropriate P97 activity.

Additional diseases that can be treated according to the methods of theinvention include in addition to cancer, auto-immune disorders,metabolic diseases, infection diseases, neurological diseases, graftversus host disease and other hereditary diseases outlined here:abeta-lipoproteinema, acerulopasminemia, alpha-1-antichymotrypsin (ACT)deficiency, aspartylglucosaminuria, autosomal dominant retinitispigmentosa, brugada syndrome, Charcot-Marie-Tooth syndrome, congenitaladrenal hyperplasia, congenital chloride diarrhea, congenitalhypothyroidism, congenital long QT syndrome, congenital nephriticsyndrome, congenital sucrase-isomaltase deficiency, Crigler-Najiar typeII, cystic fibrosis, diabetes mellitus, diastrophic displasia,Dubin-Johnson syndrome, Fabri disease, familial chylomicronemia,familial glucocorticoid deficiency, familial hypercholesterolemia,Gaucher disease, heavy chain disease, hereditary emphysema, hereditaryemphysema with liver injury, hereditary hemochromatosis, hereditaryhypofibrinogenemia, hereditary myeloperoxidase, hereditaryspherocytosis, hirschprung disease, hypogonadotropic hypogonadism,infantile systemic hyalinosis, infentile neuronal ceroid lipofuscinosis,laron syndrome, liver failure, marfan syndrome, medullary cystic kidneydisease, familial juvenile hyperuricemic nephropathy, Menkes disease,nephrogenic diabetes, neurohypophyseal diabetes insipidus,oculocutaneous albinism, osteogenesis imperfect. Pelizaeus-Merzbacherdisease, Pendred syndrome, persistent hyperinsulinemic hypoglycemia ofinfancy, primary hypothyroidism, Protein C deficiency, pseudoachondroplawith multiple epiphyseal dysplasia, severe congenital neutropenia,Stargardt-like macular dystrophy, steroid-resistant nephrotic syndrome,Tay-Sachs. Type I hereditary angioedema, tyroxine binding globulindeficiency, von Willebrand disease type IIA, X-linked Charot-Marie-Toothdisease, X-linked hypophosphatemia. Alzheimer disease autosomalrecessive juvenile parkinsonism, combined factors V and VIII deficiency,cranio-lenticulo-sutural dysplasia, hypotonia and dysmorphism, inclusionbody myopathy Paget's disease of the bone and frontotemporal dementia(IBMPFD), lipid absorption disorders, Marinesco-Sjoegren syndrome,Parkinson, polycystic liver disease, spondylo-epiphyseal dysplasiatarda, Walcott-Rallison syndrome and Lou Gehrig's disease (ALS).

In various embodiments, compounds of the invention may be used to treatneoplastic growth, angiogenesis, infection, inflammation,inunune-related diseases, ischemia and reperfusion injury, multiplesclerosis, rheumatoid arthritis, neurodegenerative conditions, orpsoriasis.

Neoplastic growth may include cancer. Suitably, the present inventionrelates to a method for treating or lessening the severity of a cancerselected from: brain (gliomas), glioblastomas, breast, Wilm's tumor,Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon,head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic,prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,lymphoblastic T cell leukemia, chronic myelogenous leukemia, chroniclymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia, chronic neutrophilic leukemia, acutelymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cellleukemia, mantle cell leukemia, multiple myeloma megakaryoblasticleukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocyticleukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma,non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt'slymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelialcancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer,renal cancer, mesothelioma, esophageal cancer, salivary gland cancer,hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccalcancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) andtesticular cancer.

In various embodiments, the cancer is selected from brain cancer(gliomas), glioblastomas, breast cancer, colon cancer, head and neckcancer, kidney cancer, lung cancer, liver cancer, melanoma, ovariancancer, pancreatic cancer, prostate cancer, sarcoma and thyroid cancer.

In various embodiments, the cancer to be treated is associated with theproteasome. See Voorhees et al., The Proteasome as a Target for CancerTherapy, Clinical Cancer Research, vol. 9, 6316-6325, December 2003,incorporated by reference in its entirety. In various embodiments, thecancer is associated with a particular target, such as NFkB, p44/42MAPK. P-gp, TopI, TopIIalpha.

In various embodiments, the cancer is a solid tumor. In variousembodiments, the cancer is selected from multiple myeloma, metastaticbreast cancer, non-small cell lung cancer, prostate cancer, advancedcolorectal cancer, ovarian or primary peritoneal carcinoma, hormonerefractory prostate cancer, squamous cell carcinoma of the head andneck, metastatic pancreatic adenocarcinoma, gastroesophageal junction orstomach, or non-Hodgkin's lymphoma.

A method of using the compounds described herein for treating a disordercharacterized by an inappropriate level of proteasome activity, or inwhich a reduction of the normal level of proteasome activity yields aclinical benefit. This disorder can include cancer or immune disorderscharacterized by excessive cell proliferation or cellular signaling.Among cancers, this includes human cancers that overexpress c-Myc orexpress an oncogenic form of the K-Ras protein.

Neurodegenerative diseases and conditions may include without limitationstroke, ischemic damage to the nervous system, neural trauma (e.g.,percussive brain damage, spinal cord injury, and traumatic damage to thenervous system), multiple sclerosis and other immune-mediatedneuropathies (e.g., Guillain-Barre syndrome and its variants, acutemotor axonal neuropathy, acute inflammatory demyelinatingpolyneuropathy, and Fisher Syndrome), HIV/AIDS dementia complex,axonomy, diabetic neuropathy. Parkinson's disease, Huntington's disease,ALS, multiple sclerosis, bacterial, parasitic, fungal, and viralmeningitis, encephalitis, vascular dementia, multi-infarct dementia,Lewy body dementia, frontal lobe dementia such as Pick's disease,subcortical dementias (such as Huntington or progressive supranuclearpalsy), focal cortical atrophy syndromes (such as primary aphasia),metabolic-toxic dementias (such as chronic hypothyroidism orB 12deficiency), and dementias caused by infections (such as syphilis orchronic meningitis). Compounds of the invention may be used to treatAlzheimer's disease, including administering to a subject an effectiveamount of an agent or composition (e.g., pharmaceutical composition)disclosed herein.

Compounds of the invention may be used to treat cachexia andmuscle-wasting diseases. Compounds of the invention may be used to treatsuch conditions wherein the condition is related to cancer, chronicinfectious diseases, fever, muscle disuse (atrophy) and denervation,nerve injury, fasting, renal failure associated with acidosis, diabetes,and hepatic failure.

Compounds of the invention can be used to treat hyperproliferativeconditions such as diabetic retinopathy, macular degeneration, diabeticnephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, biliaryatresia, congestive heart failure, scleroderma, radiation-inducedfibrosis, and lung fibrosis (idiopathic pulmonary fibrosis, collagenvascular disease, sarcoidosis, interstitial lung diseases and extrinsiclung disorders). The treatment of burn victims is often hampered byfibrosis, thus, an additional embodiment of the application is thetopical or systemic administration of the inhibitors to treat burns.Wound closure following surgery is often associated with disfiguringscars, which may be prevented by inhibition of fibrosis. Thus, incertain embodiments, the application relates to a method for theprevention or reduction of scarring.

Compounds of the invention can be used to treat ischemic conditions orreperfusion injury for example acute coronary syndrome (vulnerableplaques), arterial occlusive disease (cardiac, cerebral, peripheralarterial and vascular occlusions), atherosclerosis (coronary sclerosis,coronary artery disease), infarctions, heart failure, pancreatitis,myocardial hypertrophy, stenosis, and restenosis.

Compounds of the invention can be used for the inhibition of TNFalpha toprevent and/or treat septic shock.

Compounds of the invention can be used for inhibiting antigenpresentation in a cell, including exposing the cell to an agentdescribed herein. A compound of the invention may be used to treatimmune-related conditions such as allergy, asthma, organ/tissuerejection (graft-versus-host disease), and auto-immune diseases,including, but not limited to, lupus, rheumatoid arthritis, psoriasis,multiple sclerosis, and inflammatory bowel diseases (such as ulcerativecolitis and Crohn's disease). Thus, a further embodiment is a method formodulating the immune system of a subject (e.g., inhibiting transplantrejection, allergies, auto-immune diseases, and asthma), includingadministering to the subject an effective amount of a compound of theinvention.

Compounds of the invention can be used in methods for altering therepertoire of antigenic peptides produced by the proteasome or otherprotein assembly with multicatalytic activity.

Compounds of the invention can be used in methods for inhibitingIKB-alpha degradation, including contacting the cell with an agentidentified herein. A further embodiment is a method for reducing thecellular content of NF-KB in a cell, muscle, organ, or subject,including contacting the cell, muscle, organ, or subject with a compoundof the invention.

Compounds of the invention can be used in methods for affectingcyclin-dependent eukaryotic cell cycles. Compounds of the invention canbe used in methods for treating a proliferative disease in a subject(e.g., cancer, psoriasis, or restenosis). Compounds of the invention canbe used for treating cyclin-related inflammation in a subject.

One embodiment is a method for treating p53-related apoptosis, includingadministering to a subject an effective amount of a compound of theinvention.

In another embodiment, the compounds of the present application areuseful for the treatment of a parasitic infection, such as infectionscaused by protozoan parasites. In certain such embodiments, the agentsare useful for the treatment of parasitic infections in humans caused bya protozoan parasite selected from Plasmodium sps., Trypanosoma sps.,Leishmania sps., Pneumocystis carinii, Toxoplasma gondii, Entamoebahistolytica, Entamoeba invadens, and Giardia lamblia. In certainembodiments, the agents are useful for the treatment of parasiticinfections in animals and livestock caused by a protozoan parasiteselected from Plasmodium hermani, Cryptosporidium sps., Echinococcusgranulosus, Eimeria tenella, Sarcocystis neurona, and Neurospora crassa.Other compounds useful as proteasome inhibitors in the treatment ofparasitic diseases are described in WO 98/10779, which is incorporatedherein in its entirety.

In particular, the methods of treatment include inhibiting, arresting,ameliorating, minimizing and/or eliminating malconditions associatedwith the inability of cells to metabolize, degrade or otherwise removeubiquitin tagged proteins and peptides because the tag has been cleaved,degraded, removed or otherwise rendered disfunctional as a result of P97metalloprotease domain activity. Included are methods in which a humandisorder characterized by abnormal regulatory peptide degradationresulting in excessive cell proliferation or cell signaling. The methodsare directed to administration of an effective amount of a compound orpharmaceutical formulation disclosed above so that the abnormalregulatory peptide degradation is ameliorated, reduced or inhibited. Inparticular, the human disorders include a cancer or immune disorder, acancer resulting from overexpression of c-Myc or expression of anoncogenic form of the K-Ras protein. The methods also include inhibitionor amelioration of P97 metalloprotease domain activity in a humanpatient suffering from abnormal P97 metalloprotease domain activity onubiquitin modified proteins. As described above, these methods involveadministering to the patient an effective amount of a compound orpharmaceutical formulation disclosed above so that the abnormal P97metalloprotease domain activity is ameliorated, reduced or inhibited.

Diagnostics

Various cellular proteins are subject to proteolytic processing duringmaturation or activation. The compositions identified herein can also beuseful as diagnostic agents (e.g., in diagnostic kits or for use inclinical laboratories) for screening for proteins (e.g., enzymes,transcription factors) processed by hydrolases, including theproteasome. The agents are also useful as research reagents forspecifically binding the X/MB 1 subunit or alpha-chain and inhibitingthe proteolytic activities associated with it. For example, the activityof (and specific inhibitors of) other subunits of the proteasome can bedetermined.

Compounds of the invention identified herein can be used to determinewhether a cellular, developmental, or physiological process or output isregulated by proteolytic activity. One such method includes obtaining anorganism, an intact cell preparation, or a cell extract; exposing theorganism, cell preparation, or cell extract to an agent identifiedherein; exposing the agent-exposed organism, cell preparation, or cellextract to a signal and monitoring the process or output. See, forexample, U.S. Pat. No. 7,741,432.

The compounds of this invention may used as a part of a diagnosticassay. For instance cells from a patient may be obtained and an assaymay be performed to determine whether the compounds of the invention arelikely to be effective therapeutic compounds for that patient. The cellsobtained from the patient can be for instance cancerous cells from atumor. The cells can be cultured and compounds of the invention can beapplied to determine how the cancerous cells respond.

The diagnostics aspect of the invention also includes an assay for thedetermination of inhibition of P97 activity. The assay involvescombining a P97 enzymatic material with a protein substrate anddetermining whether a potential inhibitory candidate will function inthis assay to lessen the enzymatic activity. The P97 enzymatic materialis either a standard or taken from a patient's cells. The proteinsubstrate similarly is either standard or taken from a patient's cells.In particular, the protein substrate is selected from the groupconsisting of a protein modified by a ubiquitin, a protein modified by aubiquitin-like modifier and a protein modified by a ubiquitin chain thatcan be isolated from a patient's cells. The combination of the P97enzymatic material and the protein substrate produces an enzymaticmedium. For this medium, the protein substrate is modified with a tagthat is detectable by measurement of molecular weight, spectroscopicinteraction or chromatographic R_(f) determination,

Following the isolation and tagging, the enzymatic medium is manipulatedto conduct a first measurement of the enzymatic medium relative to theprotein substrate alone wherein the first measurement is made by adetection of the tag.

Following the first measurement procedure, a potential inhibitorycandidate is combined with the tagged protein substrate and the P97enzymatic material is added to produce a candidate medium.

The candidate medium is manipulated to conduct a second measurement ofthe candidate medium relative to the protein substrate alone wherein thesecond measurement is made by detection of the tag.

Finally, the ability of the inhibitory candidate to be effectivetreatment for the patient in need is assessed by comparing the first andsecond measurements to identify a candidate that demonstrates at leastabout a 50% inhibition at a concentration of no more than 500 micromolarin the candidate medium, the difference between the first and secondmeasurements being at least about 50% with the second measurement beinggreater than the first measurement.

Specific Embodiments of the Fused Pyrimidine Compounds of Formula I

Embodiments of the fused pyrimidine compounds of Formula I include thespecific compounds named in the following Table according to their IUPAC(International Union of Pure and Applied Chemistry) nomenclature. Allcompounds of these tables can be synthesized according to the syntheticschemes outlined below and will demonstrate appropriate biologicalactivity in one or more Biological Assays described herein. Table Idivides these embodiments into three groups: preferred, more preferredand most preferred.

TABLE I LIST OF INDIVIDUAL COMPOUNDS Preferred1-(4-((3,5-difluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohqpta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-(hydroxymethyl)-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-(hydroxymethyl)-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,8-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,8-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide2-(4-(aminomethyl)-2-methyl-1H-indol-1-yl)-N-benzyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-amine2-(aminomethyl)-1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indole-4-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamideN-benzyl-2-(2-methyl-1H-indol-3-yl)-5,6,7,8-tetrahydroquinazolin-4-amine(1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6-dimethyl-pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxylicacid1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-5,6,7,8-tetrahydroquinazolin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amineN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahyrdropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-IH-benzo[d][1,2,3]triazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahyrdro-5H-pyrimido[5,4-c]azepin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahyrdro-5H-pyrimido[5,4-c]azepin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahyrdro-5H-pyrimido[4,5-c]azepin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-8-methyl-6,7,8,9-terrahydro-5H-pyrimido[4,5-c]azepin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)isobenzofuran-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2H-isoindole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylindolizine-5-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-terahydro-5H-pyrimido[4,5-b]azepin-2-yl)benzo[c]thiophene-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)isobenzofuran-4-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fiuorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydbro-5H-pyrimido[4,5-d]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((thiophen-2-ylmethyl)amino)-9-methyl-6,7,8,9-tetrahydro-5Hpyrimido[4,5-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-[1,2,3]triazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-[1,2,3]triazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide 3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-[1,2,3]triazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide 3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-[1,2,3]triazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-[1,2,3]triazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-[1,2,3]triazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-[1,2,3]triazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide 3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-[1,2,3]triazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-[1,2,3]triazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-[1,2,3]triazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylbenzo[b]thiophene-7-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylindolizine-8-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)benzo[c]isothiazole-7-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)benzo[c]isoxazole-7-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)benzo[d]isothiazole-7-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)benzo[d]isoxazole-7-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide 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preferred:1-(4-((3,5-difluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-(hydroxymethyl)-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-(hydroxymethyl)-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,8-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,8-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide2-(4-(aminomethyl)-2-methyl-1H-indol-1-yl)-N-benzyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-amine2-(aminomethyl)-1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indole-4-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamideN-benzyl-2-(2-methyl-1H-indol-3-yl)-5,6,7,8-tetrahydroquinazolin-4-amine(1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6-dimethyl-pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxylicacid1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-5,6,7,8tetrahydropyrido[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-5,6,7,8-tetrahydroquinazolin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amineN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-5-carboxamide1-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydrooxepino[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,6,7,9-tetrahydrooxepino[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,8,9-tetrahydrooxepino[4,5-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,7,8,9-tetrahydrooxepino[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine-8-carboxamide3-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)imidazo[1,5-a]pyridine-8-carboxamide3-(4-(benzylamino)-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepin-2-yl)-2-methyl-1H-indole-7-carboxamide Most preferred:1-(4-((3,5-difluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-((thiophen-2-ylmethyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-(hydroxymethyl)-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-5-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-(hydroxymethyl)-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,8-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6,8-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-6-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-7-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-6-fluoro-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide1-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide1-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide1-(4-(benzylamino)-8-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide2-(4-(aminomethyl)-2-methyl-1H-indol-1-yl)-N-benzyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-amine2-(aminomethyl)-1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indole-4-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methylbenzofuran-7-carboxamide3-(4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-5-methyl-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-7-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamideN-benzyl-2-(2-methyl-1H-indol-3-yl)-5,6,7,8-tetrahydroquinazolin-4-amine(1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-5,6-dimethyl-pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol(1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methanol1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxylicacid1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxylic acid2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-5,6,7,8-tetrahydroquinazolin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-(3-fluorobenzyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine2-(4-(aminomethyl)-1H-indazol-1-yl)-N-benzyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amineN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)-2-methyl-propanamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)acetamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)ethanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)methanesulfonamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propanamideN-((1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazol-4-yl)methyl)propane-2-sulfonamide

Synthetic Methods

The following section describes the preparation of representativecompounds of the invention in greater detail. The following examples areoffered for illustrative purposes, and are not intended to limit theinvention in any manner. Those of skill in the art will readilyrecognize a variety of noncritical parameters which can be changed ormodified to yield essentially the same results.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thesyntheses of the compounds and methods of use thereof described herein.Although certain exemplary embodiments are depicted and describedherein, it will be appreciated that compound of the invention can beprepared according to the methods generally available to one of ordinaryskill in the art. All of the above-cited references and publications arehereby incorporated by reference.

Synthetic Preparation

The novel compounds of the present invention can be prepared in avariety of ways known to one skilled in the art of organic synthesis.The compounds of the present invention can be synthesized using themethods as hereinafter described below, together with synthetic methodsknown in the art of synthetic organic chemistry or variations thereon asappreciated by those skilled in the art.

Preparation of compounds can involve the protection and deprotection ofvarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene and Wuts, Protective Groups in OrganicSynthesis, 44th. Ed., Wiley & Sons, 2006, as well as in Jerry March,Advanced Organic Chemistry, 4^(th) edition, John Wiley & Sons,publisher, New York, 1992 which are incorporated herein by reference intheir entirety.

The fused pyrimidine scaffolds can be prepared by the literature methodscited in the following text. The following schemes depict established,known syntheses of these scaffolds.

The Het moiety and the amine substituents of the fused pyrimidinescaffolds can be synthesized and attached to these scaffolds by theliterature methods cited in the following text. The following schemesdepict the known techniques for accomplishing this joinder.

General Synthetic Schemes for Fused Pyrimidines

Compounds of the present invention can be synthesized using thefollowing methods. General reaction conditions are given and reactionproducts can be purified by general known methods includingcrystallization, silica gel chromatography using various organicsolvents such as hexane, cyclohexane, ethyl acetate, methanol and thelike, preparative high pressure liquid chromatography or preparativereverse phase high pressure liquid chromatography.

A cyclic ketoester of the general structure A1 can be reacted with ureain the presence of acid such as HCl in a solvent such as ethanol atrefluxing temperature for 2 to 24 hours to give the pyrimidine dione A2.Pyrimidinedione A2 can be reacted with an excess of POCl₃ at reflux for3-12 hours optionally in the presence of a tertiary amine such astriethyl amine to give the fused dicholorpyrmidine of the generalstructure A3. Other chlorinating agents such as thionyl chloride or PCl₅can be substituted for POCl₃. A3 can be reacted with excess amounts ofvarious substituted amines at temperatures ranging from room temperatureto reflux in a solvent such as acetonitrile or dimethylfomamide to give4-amino-2-chloro fused pyrimidines of the general structure A.

Similarly, 2-Cl-5,7-dihydrofuro[3,4-d]pyrimidin-4-amines BA can beprepared for the corresponding ketoester BA2, the later can be made fromtreatment 2-hydroxyacetate with ethyl acrylate in the presence of astrong base such as sodium hydride.

2-(2,4,6-trichloropyrimidin-5-yl)ethanol BB1 can be converted into thedichloride BB2 through intramolecular cyclization in the presence of astrong base such as sodium hydride at room temperature. Similarly, thelatter can react with amines to yield2-chloro-5,6-dihydrofuro[2,3-d]pyrimidin-4-amines BB.

Tetrahydropyran-4-one BC1 can react with dimethylcarbonate in thepresence of sodium hydride to 4-oxotetrahydro-2H-pyran-3-carboxylateBC2, the latter can be then converted into the corresponding diol BC4 ina two-step procedure through the intermediate of4-ureido-5,6-dihydro-2H-pyran-3-carboxylate BC3. Similarly, the diol canbe converted into2-chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amines BC.

Dihydrofuran-2(3H)-one BD1 can be converted into 4-hydroxybutanoate BD3by hydrolysis using a strong base such as potassium hydroxide followedby treatment with an alkylbromide. It can react with2-propionyldiazenecarbaldehyde in the presence of Rh₂(OAc)₄ to yield4-(2-ethoxy-2-oxoethoxy)butanoate BD4, the latter can be converted into3-oxotetrahydro-2H-pyran-4-carboxylate BD5 by treatment with potassiumtert-butoxide. Then similar approach as used in preparation of BC cantransfer the ketoester into2-chloro-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amines BD.

Tetrahydro-2H-pyran-2-one BE1 can be converted into2,4-bis(methylthio)-pyrimidine BE2 by a single step reaction withthiocyanatomethane in the presence of TFA though its yield is relativelylow. The latter is then oxidized by m-CPBA into disulfone BE3. Thesulfone can be hydrolysized into the diol BE4 using aqueous sodiumhydroxide solution. Similarly, it can be then converted into2-chloro-6,7-dihydro-51l-pyrano[2,3-d]pyrimidin-4-amines BE.

Commercially available Boc-protected2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine CA1 can be converted into thecorresponding 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-aminesCA in a similarly approach.

2-(2,4,6-trichloropyrimidin-5-yl)acetaldehyde CB1 can react with aminessuch as methylamine through reductive animation in the presence ofNaBH3CN to yield 2,4-dichloride CB2 according to PCT Int. Appl.,2011152485, the latter can be easily converted into2-chloro-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-amines CB in theaforementioned approach.

Benzyl protected 4-oxopiperidine-3-carboxylate CC1 can be converted intoits diol CC2 by treatment with urea under basic conditions such assodium methoxide. It is then transferred into the dichloride CC3 priorto switch protection group from benzyl group into Boc group consideringit'd be challenge to remove benzyl group selectively oncearomaticmethylamino group at 4-position of the pyrimidine. Similarly,Boc-protected dichloride CC5 can react with amines to yieldBoc-protected 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-aminesCC.

Similarly, Boc-protected2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amines CD can beprepared from 1-benzyl-3-oxopiperidine-4-carboxylate CD1.

Region isomers CE,2-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-amines, can beprepared in couple of different approaches. 2-aminonicotinic acid CE1can react with urea followed by hydrolysis to yieldpyrido[2,3-d]pyrimidine-2,4-diol CE2, the latter can be easily convertedinto the dichloride CE3. CE3 can be selectively reduced into2,4-dichloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine CE4 underhydrogen of one atmosphere pressure in the presence of PtO₂, thought theyield in general is relatively poor. Then introduction of Boc protectiongroup on the amino group and replacement of 4-chloride with amines canyield CE. Alternatively, treatment CE3 with amines first followed byreduction by hydrogen of higher pressure can achieve better yield.

A similar approach can be utilized to prepare another set of regionisomers, 2-chloro-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amines CF.3-aminopicolinic acid CF1 is the starting material. Due to substitutionon 4-position of the pyrimidine, it can be challenge to introduceprotection groups such as Boc to protect the amino group in a reasonableyield, instead, small alkyl groups such as methyl can be easilyinserted.

5,6,7,8-tetrahydropyridopyrimidin-4-amines with alkyl group on theircarbon of the saturated ring can also be prepared using theaforementioned approaches as long as their corresponding ketoester canbe prepared. For example,1-benzyl-5-methyl-4-oxopiperidine-3-carboxylate can be prepared in athree-step procedure from methyl methacrylate CG1,3-(benzylamino)-2-methylpropanoate can be prepared from Michael additionbetween methacrylate CG1 and benzylamine, similarly one more Michaeladdition with acrylate can yield3-(benzyl(3-methoxy-3-oxopropyl)amino)-2-methylpropanoate CG3. Anintramolecular cyclization of CG3 in presence of sodium hydride atreflux can yield 1-benzyl-5-methyl-4-oxopiperidine-3-carboxylate CG4.Then a similar route as aforementioned can achieve2-chloro-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amines CG.Similar strategy can be utilized to preparetetrahydropyridopyrimidin-4-amines with alkyl group substituted on otherpositions or chiral derivatives if chiral acrylates were used asstarting material.

2,4-Dibromo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine CH1 can bereacted with an amine to selectively yield the intermediate CH2, thelater can be Boc-protected by reaction with Boca hydride to yield CH.

A general synthetic approach to install benzo[d]imidazole DA1 throughits 1-position into the 2-position of fused pyrimidine to yield thedesired molecules DA is Pd-based coupling reaction. A common conditionis Pd(dba)₂ as a transition metal catalyst and X-phos as a ligand andcesium carbonate as a base and dioxane an organic solvent. The reactiontemperature varies from the room temperature to reflux. For example if Yis Boc-protected nitrogen, an extra step to deBoc can be achieved. Forexample if R¹ is a nitrile (CN) it can be converted to an amide in thepresence of urea hydrogen peroxide (UHP). Alternatively, in some casesof R⁴ is alkoxy or amino groups, coupling reaction can be take placebetween the 2-chloro-pyrimidine DA0 and benzene-1,2-diamines DA2 suingPd(OAc)₂ as the catalyst and CsCO₃ as the base, then cyclization canoccur with either bromocyanide or tetramethoxymethane.

Coupling to a solution of the substituted pyrimidine DA0 with an indoleor inadazole DB1 can be effective to achieve the desired molecules DBusing methods similar to that described in Zhou, H.-J, et. al. WO2014015291. To a solution of substituted pyrimidine such as compound DA0is added a indole or a substituted ones such as compound DB1 and a basesuch as sodium carbonate or cesium carbonate, in the presence of apalladium catalyst such as Pd(OAc)₂ and a ligand such astriphenylphosphine in a solvent such as dioxane and the reaction canoptionally be heated to reflux for up to 48 hours.

Compounds containing the structure of1-pyrimidin-2-yl-1,2,3-benzotriazoles DC can be produced using methodssimilar to those described in Zhou, 1H.-J, et. al. WO 2014015291 andOhlmeyer, Michael J, et al WO 2008060301 and as described above by usinga substituted 1,2,3-benzotriazole DC1.

Under various conditions such as NBS in DMF, bromination of3-unsubstituted intermediates DD1 (X═O, S, either substituted orproperly protected nitrogen) would take place region-selectively ontheir 3-position to yield 3-Br-substituted intermediates DD2. They thencan be converted into boronic esters DD4 by treatment with boronic esterDD3 under various conditions. Then Pd-based coupling reaction similar tothose described in Zhou, H.-J, et. al. WO 2014015291 betweenintermediates DD4 and DA0 provided the desired molecules. For example ifY or A is protected nitrogen, an extra step to deprotection can beachieved using reported conditions.

The key intermediate DE1, tributyl-2-pyrmidinyltin can be prepared fromthe intermediates DA0 following the similar procedure in the reference(Castanedo Georgette et al, PCT Int. Appl., 2010138589). Bromonation canoccur selectively into the 3-position of these 5,6-bicycloaromaticrings. Then Pd-based coupling reaction similar to those described inZhou, H.-J, et. al. WO 2014015291 between intermediates DE1 and DE2provided the desired molecules DE. For example if Y or A is protectednitrogen, an extra step to deprotection can be achieved using reportedconditions.

Bromonation can occur selectively into the 3-position ofimidazo[1,5-a]pyridine DF1. Then Pd-based coupling reaction similar tothose described above between intermediates DE1 and DF2 provided thedesired molecules DF. For example if Y is protected nitrogen, an extrastep to deprotection can e achieved using reported conditions.

Alternatively, bromides DF2 can be converted into boronic esters DF3 bytreatment with boronic ester DD3 under various conditions. Then Pd-basedcoupling reaction similar to those described above between intermediatesDF3 and DA0 provided the desired molecules. For example if Y or A isprotected nitrogen, an extra step to deprotection can be achieved usingreported conditions.

Imidazo[1,5-a]pyridin-3(2H)-one DG1 can be converted into its triflateDG2. Then Pd-based coupling reaction similar to those described abovebetween intermediates DE1 and DG2 provided the desired molecules DG. Forexample if Y is protected nitrogen, an extra step to deprotection can beachieved using reported conditions.

Alternatively, substituted imidazo[1,5-a]pyridine-3-carboxylate estersDG3 can be prepared by various methods including those outlined in Chen.Shaoqing et al WO 2013030138, Bilodeau, and Mark T, et al WO 2008085302.An imidazo[1,5-a]pyridine-3-carboxylate ester DG3 can be converted intothe corresponding amidine DG4 using aminochloromethyl aluminum in anorganic solvent such as toluene at a temperate between ambient and 100°C. as described in Brockunier L, et. al. WO 2010065275 and (GargiapatiR. S. Tetrahedron Letters 1990, 31, 1969. The resultingimidazo[1,5-a]pyridine-3-carboxamidine DG4 can be reacted with theaforementioned ketoesters DG5 in the presence of a catalytic amount of abase such as sodium ethoxide in ethanol at reflux to give thepyrimidin-4-ol DG6. The latter can be converted into the desiredmolecules DG using the methods described above.

Imidazo[1,2-a]pyridin DH3 can be prepared by treatment 2-aminopyridineDH1 with aldehydes or ketones DH2 by a method similar to those describedin described in the references such as Ebetino, rank Hallock e al. PCTInt. Appl., 2010033978. Iodination with NIS can yield3-I-Imidazo[1,2-a]pyridine DH4 by a method similar to those described indescribed in the references such as Bifulco, Neil, Jr, et al. PCT Int.Appl., 2014011900. [1,2,4]triazolo[4,3-a]pyridine-8-carbonitrile DH7 canbe prepared by substituted pyridine DH5 in a two-step procedures,reaction with hydrazine followed by treatment with triethoxymethane by amethod similar to those described in described in the references such assuch as Allen, Shelley ct al. PCT Int. Appl., 2010022076; Polts, K. T,and Burton, H. R., Journal of Organic Chemistry, 31(1), 251-60; 1966.Then bromination with NBS can yield the intemiediate DH8. DH4 or DH8 canbe converted into boronic esters DH9 then by treatment with boronicester DD3 under various conditions. Then Pd-based coupling reactionsimilar to those described above between intermediates DH9 and DA0provided the desired molecules DH. Alternatively, Pd-based couplingreaction similar to those described above between intermediates DE1 andDH4 or DH8 provided the desired molecules DH as well. For example if Yis protected nitrogen, an extra step to deprotection can be achievedusing reported conditions.

Various methods can be used to prepare substituted3-pyrimidin-2-ylpyrazolo[1,5-a]pyridines DI1 (Z=CR⁴) as outlined inTsuchiya, et. al. Chemical & Pharmaceutical Bulletin 1983, 31, 4568;Hajos, G, and Riedl. Z. Science of Synthesis, 2002, 12, 613 andAboul-Fadl, T, et al. Synthesis, 2000, 12, 1727-1732. Various methodscan be used to prepare substituted [1,2,3]triazolo[1,5-a]pyridine DI1(Z=N) as outlined in Latham, Elliot J, and Stanforth, Stephen P. Journalof Heterocyclic Chemistry, 32(3), 787-9; 199; Sheng et al, OrganicLetters, 14(14), 3744-3747; 2012 and Prakash, Om et al, SyntheticCommunications, 30(3), 417-425; 2000. Iodination with NIS can yield3-iodo-pyrazolo[1,5-a]pyridine D12 by a method similar to thosedescribed in described in the references such as Bifulco, Neil, Jr, etal. PCT Int. Appl., 2014011900; Wan, Huixin et al, PCT Int. Appl.,2013170774, 21 Nov. 2013. D12 can be then converted into boronic estersDI3 then by treatment with boronic ester DD3 under various conditions.Then Pd-based coupling reaction similar to those described above betweenintermediates D13 and DA0 provided the desired molecules DI.Alternatively, Pd-based coupling reaction similar to those describedabove between intermediates DE1 and DI2 provided the desired moleculesDI as well. For example if Y is protected nitrogen, an extra step todeprotection can be achieved using reported conditions.

1-Bronmo-lindolizine DJ2 can be prepare from substituted pyridine usingmethods as outlined in Iizuka, Masato and Shimizu, Kazuo. PCT Int.Appl., 2012043638. DJ2 can be then converted into boronic esters D13then by treatment with boronic ester DD3 under various conditions. ThenPd-based coupling reaction similar to those described above betweenintermediates DJ3 and DA0 provided the desired molecules DJ.Alternatively, Pd-based coupling reaction similar to those describedabove between intermediates DE1 and DJ2 provided the desired moleculesDI as well. For example if Y is protected nitrogen, an extra step todeprotection can be achieved using reported conditions.

Pd-based coupling reaction between DJ1 and DA0 using approaches similarto those described above provided the desired molecules DK. For exampleif Y is protected nitrogen, an extra step to deprotection can beachieved using reported conditions.

The boronic ester of 211-isoindole DL3 can prepared from substituted1,2-dimethylbenzene DL1 following the procedure in the reference(Ohmura. Toshimichi et al Journal of the American Chemical Society,131(17), 6070-6071; 2009). Then Pd-based coupling reaction similar tothose described above between intermediates DL3 and DA0 provided thedesired molecules DL. For example if Y is protected nitrogen, an extrastep to deprotection can be achieved using reported conditions.

The key intermediates DM3, benzo[c]thiophen-1-yltrimethylstannane canprepared from the intermediates DL2 following the similar procedure inthe reference (Kawabata, Kohsuke and Goto, Hiromasa, Journal ofMaterials Chemistry, 22(44), 23514-23524; 2012). Then Pd-based couplingreaction similar to those described above between intermediates DM3 andDA0 provided the desired molecules DM. For example if Y is protectednitrogen, an extra step to deprotection can be achieved using reportedconditions.

The key intermediates DN3, tributyl(isobenzofuran-1-ylistannane canprepared from the intermediates DN2, which can be prepared from lactoneDN1. Then Pd-based coupling reaction similar to those described abovebetween intermediates DN3 and DA0 provided the desired molecules DN. Forexample if Y is protected nitrogen, an extra step to deprotection can beachieved using reported conditions.

Substituted 3-methoxybenzo[c]isoxazoles DO2 can prepared from2-aminobenzoates DO1 following the similar procedure in the referencessuch as Chauhan, Mohinder S, and McKinnon, David M., Canadian Journal ofChemistry, 53(9), 1336-42; Smalley, R. K., Science of Synthesis, 11,337-382; 2002. Then demethylation and conversion hydroxyl into triflategroup can yield the intermediate DO3. Substituted benzo[c]isothiazoleDO6 can prepared from substituted o-toluidine DO04 following the similarprocedure in the references such as Puetz, Claudia et al, Eur. Pat.Appl., 1352910. Then bromination with BNS can selectively into Br intoits position DO7. Then Pd-based coupling reaction similar to thosedescribed above between intermediates DO3 or DO7 and DA0 provided thedesired molecules DO. For example if Y is protected nitrogen, an extrastep to deprotection can be achieved using reported conditions.

In some cases the desired compounds DP1 prepared in Schemes 5-18 abovecan have a nitrile substitution at the position indicated in Scheme 19.This substituent can be converted to the corresponding carboxamide.Nitriles DP1 are dissolved in a 1/10 ratio of water/DMSO and treatedwith urea-hydrogen peroxide (UHP) and a base such as potassiumcarbonate. Reaction mixture is stirred at room temperature for up to 18hours and then is poured into ice water and stirred for two hours. Theresulting solid is filtered, dried and if necessary purified by columnchromatography to give the desired amides DP2.

In some cases the desired compounds DP1 prepared in Schemes 1-18 abovecan have a nitrile substitution at the position indicated in Scheme 20.This substituent can be converted to the corresponding methylamines DP3.A solution of nitrile DP1 in an aprotic organic solvent such as THF istreated with LAH and the resulting mixture is stirred for up to 18hours. The reaction mixture is treated with 15% NaOH in water and thereaction is stirred for one hour and is then filtered. The THF isremoved under reduced pressure to give the product DP3 which can befurther purified by column chromatography.

In some cases the desired compounds DP1 prepared in Schemes 5-18 abovecan have a carboxylate ester at the position indicated in Scheme 21.This functionality can be readily converted to the corresponding acidsDP4 or substituted amides DP5 using standard methodology.

In some cases the desired compounds DP1 prepared in Schemes 5-18 abovecan have a nitrile at the position indicated in Scheme 22. Thisfunctionality can be readily converted to the corresponding amines DP7or alcohols or ethers DP8 using standard methodology through theintermediate—aldehydes DP6.

In some cases the desired compounds DP9 prepared in Schemes 5-18 abovecan have an aldehyde at the position indicated in Scheme 23. Thisfunctionality can be readily converted to the corresponding alcohols orethers DP10 or amines DP11 or using standard methodology.

Biological Assays

The biological activities of the fused pyrimidine compounds of theinvention can be determined by their examination in in vitro andcellular assays using protocols well established to identify and selectcompounds that will exhibit anti-cancer activity. The present inventionfocuses upon the ability of the fused pyrimidine compounds to intersectwith the p97 proteosome complex. As described in the Background, thefunction of the p97 complex is essential for continued cellularviability. Inhibition of the activity of the complex will cause proteinbuild-up in the cell and consequent apoptosis. The biological assaysallow an assessment of the biological activities of the fused pyrimidinecompounds of the invention.

The primary biological analyses are in vitro assays and cellular basedassays for determining the inhibitory capability of the fused pyrimidinecompounds of the invention of the invention against Valosin-containingprotein, i.e., p97. The assays also provide a primary indication ofbioavailability of the fused pyrimidine compounds of the invention.

The ability to inhibit the p97 complex is studied through use of a p97in vitro assay using a tagged p97 substrate pursuant to the method ofChristianson in Nat Cell Biol. (2011) 14:93 for a p97 cell-based assay.A cell based assay is used to test the anti-tumor effects of inhibitorson cultured cancer cells. This anti-tumor assay is based upon culturedcancer cells using the commercially available cell titer glo assayprovided by Promega. Additional assays enable assessment ofbioavailability through art recognized model studies designed todemonstrate the ability of the compounds of the invention to reachtarget cells in vivo. While all compounds tested displayed a degree ofanti-tumor activity, the assays also allowed identification of fusedpyrimidine compounds as candidates that may be selected for furtherexamined by in vivo anti-tumor testing in mouse, guinea pig and dogmodels. The selected candidates were shown to have highly desirablepharmacokinetic properties in these in vitro assays.

P97 ATPase Biochemical Assay

The ATPase assay is performed according the following protocol: Purifiedenzyme (20 nM p97), substrate (20 μM ATP) and a dose titration ofcompounds are mixed in buffer (50 mM TRIS pH 7.5, 20 mM MgCl₂, 0.02%TX-100, 1 mM DTT, 0.2% (v/v) glycerol) and incubated at 37° C. for 15minutes. The reaction is terminated and the level of product generatedis measured using the ADP Glo Assay Kit (Promega, Madison Wis.).Plotting product generated versus compound concentration and using afour-parameter fit model generates an IC50 value for each compounds.

P97 Cell-Based Assay

On target cell-based effects of compounds of the invention are monitoredusing the reporter cell line HEK-293 TCRα-GFP as described inChristianson ct al. Nat. Cell Biol. (2011) 14:93. Inhibition of turnoverof the TCRα-GFP reporter is a hallmark of p97 inhibition. The protocolfor TCRα-GFP monitoring reporter turnover is as follows: Reporter cellsare seeded and incubated with proteasome inhibitor MG 132 to accumulateTCRα-GFP. Subsequently, MG 132-containing media is removed and a dosetitration of compound plus cycloheximide is incubated with the cells. Atthe end of the incubation, compound and media are removed, cells arefixed and GFP fluorescence is measured by standard epifluorescentmicroscopy techniques. Plotting fluorescence versus compoundconcentration and using a four-parameter fit model generates an IC50value for each compound.

Image-analysis is used to generate quantitative data from these assaysthat can be fit to a four-parameter sigmoid curve to derive IC50 values.Substrates of the ubiquitin-proteasome system, such as p53, aremonitored after tumor cell lines are incubated with compounds forseveral hours. Accumulation of these proteins indicates an inhibition ofproteasome-mediated degradation. Accumulation of lysine-48 chain linkageof poly-ubiquitin is also monitored by immunofluorescence as anindicator of ubiquitin-proteasome system inhibition. Both LC3 and SQSTM1are mediators of autophagy. The localization and amounts of theseproteins are monitored by immunofluorescence and report on the activityand inhibition of autophagy in response to p97 inhibition.

Cultured Cancer Cell Assay

Anti-tumor effects are monitored in cultured cancer cells after severaldays of compound treatment. The cell titer glo assay (Promega) measuresthe amount of ATP present as a proxy for cellular viability. Cellularcounting is done using high-content microscopy followed by imageanalysis. A hanging drop 3D-culture system (3D Biomatrix) is usedfollowed by cell titer glo to measure growth in a tumor-likeenvironment.

Absorption Assay

The ability of compounds to be absorbed from the lumen of thegastrointestinal tract after oral administration was assessed bymeasuring their permeability through Caco-2 cell monolayers. SunD, etal., Curr. Opin. Drug Discov. Develop[(2004) 75. The in vitropermeability of compound (2 μM in Kreb's buffer or HBSS buffer with n=2)was determined using 21-day old Caco-2 cell monolayers. The permeationcoefficient was determined for both Apical to Basolateral (A to B) andBasolateral to Apical (B to A) after 120 min at 37° C. The efflux ratiowas calculated based on the ratio of permeation coefficient of B to Avs. A to B to determine the potential of compound as substrate forefflux pump (e.g. Pgp). The protocol for this Caco-2 assay and thecorresponding detailed description are provided in the followingexperimental section.

Metabolic Stability Assay

Metabolic stability of compounds can be assessed by measuring their halflives in liver microsomal preparations. Roserts, Sa, et al., Xenobiotica(2001) 37:557. Compounds are applied to a preparation of mouse livermicrosomes in the presence of NADPH and their half lives are determinedby measuring the rate of disappearance of the compounds from thepreparation by determining the concentration at 0, 15, 30 and 60 minutesusing LCMS/MS. The protocol for determining metabolic stability in amouse liver assay and the corresponding detailed description areprovided in the following experimental section.

Nonspecific Binding Assay

Many compounds are known to bind nonspecifically to proteins found inhigh abundance in the plasma. The fraction of unbound drug (freefraction) is available for interaction with targets found in tissues.Banker, M. J, et al., Curr. Drug Metab. (2008) 9:854. The ability ofcompounds to escape a chamber containing blood plasma to a chambercontaining only buffer can be assessed by measuring the concentrationthat appears in the buffer chamber and the concentration that remains inthe plasma chamber. These measurements can be used to determine thefraction of compound bound to plasma proteins and its free fraction(100-percent bound to plasma proteins). The protocol for determiningnon-specific protein binding in a plasma protein binding assay and thecorresponding detailed description are provided in the followingexperimental section.

The results of the primary assay conducted with selected fusedpyrimidine compounds of the invention show that the fused pyrimidinecompounds of the invention display significant inhibitory activity(IC₅₀) against the enzymatic action of p97 toward its natural substrate.Some of these compounds also have greater potency in cell based assaysand have in vitro pharmacokinetic properties consistent with good oralbioavailability. These results are provided below in Table II.

Examples

The following describes the preparation of representative compounds ofthe invention in greater detail. The following examples are offered forillustrative purposes, and are not intended to limit the invention inany manner. Those of skill in the art will readily recognize a varietyof noncritical parameters which can be changed or modified to yieldessentially the same results.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thesyntheses of the compounds and methods of use thereof described herein.Although certain exemplary embodiments are depicted and describedherein, it will be appreciated that compound of the invention can beprepared according to the methods generally available to one of ordinaryskill in the art. All of the above-cited references and publications arehereby incorporated by reference.

Unless otherwise noted, all solvents, chemicals, and reagents wereobtained commercially and used without purification. The 1H NMR spectrawere obtained in CDCl3, d6-DMSO, CD3OD, or d6-acetone at 25° C. at 300MHz on an OXFORD (Varian) spectrometer with chemical shift (8, ppm)reported relative to TMS as an internal standard. HPLC-MS chromatogramsand mass spectra were obtained with Shimadzu LC-MS-2020 system. Theprep-HPLC instruments used to purify some compounds were either a GilsonGX-281(Gilson) or a P230 Preparative Gradient System (Elite).Preparative chira HPLC separations were performed using an Elite P230Preparative Gradient System, a Thar Prep-80 or Thar SFC X-5. Reactionsusing microwave irriadation were performed on a CEM Discover SPinstrument.

Synthesis of1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamideFF03

To a solution of methyl 1H-indazole-4-carboxylate 2 (2.6 g, 14.7chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to givemethyl1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxylate3 (2.74 g, 45%). LRMS (M+H+) m/z: calcd 414.47; found 414.

To a solution of methyl1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carbaoxylate3 (2.74 g, 6.63 mmol) in THF (12 mL), MeOH (4 mL) and H₂O (4 mL) wasadded LiOH (836 mg, 19.9 mmol). Then the mixture was stirred at roomtemperature for 3 h. The solvent was removed and the solid was resolvedwith water, neutralized with HCl (IM) to pH=2˜3, the solid was filteredand dried to give1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxylicacid 4 (2.3 g, 87%) which was used for next step without furtherpurification. LRMS (M+H⁺) m/z: calcd 400.45; found 400.

To a solution of1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxylicacid 4 (2.3 g, 5.76 mmol) in DMF (60 mL) was added NH₄Cl (930 mg, 17.3mmol), HATU (3.3 g, 8.64 mmol) and Et₃N (2.4 mL, 17.3 mmol). Then thereaction solution was stirred at room temperature overnight. Water wasadded to the resulting solution and the solid was filtered, dried andpurified by Combiflash (dichloromethane/methanol=20:1) to give1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamideFF03 (1.6 g, 70%). LRMS (M+H⁺) m/z: calcd 399.46; found 399. HPLC purity(214 nm): 100%. ¹HNMR (300 MHz, DMSO): δ 8.61 (s, 1H), 8.38 (d, J=8.4Hz, 1H), 8.09 (s, 1H), 7.70-7.68 (m, 2H), 7.54 (s, 1H), 7.42-7.32 (m,5H), 7.24-7.23 (m, 1H), 4.74 (d, J=5.6H, 2H), 2.70-2.68 (m, 2H),2.50-2.48 (m, 2H), 1.83-1.82 (m, 2H).

Synthesis of1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamideCompound FF04

Similar procedure was utilized to the desired molecule FF04,1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamideas white solid (60 mg, 52%). LRMS (M+H⁺) m/z: calcd 400.16; found 401.HPLC purity (214 nm): 98%. ¹HNMR (400 MHz. DMSO): δ 8.63 (s, 1H), 8.39(d, J=5.4 Hz, 1H), 8.11 (hr, 1H), 7.69 (d, J=4.5 Hz, 2H), 7.56 (br, 1H),7.41-7.20 (m, 5H), 4.73 (d, J=5.4 Hz, 2H), 4.58 (s, 2H), 4.00-3.96 (m,2H), 2.77 (t, J=0.3 Hz, 2H)

Synthesis of3-(4-(benzylamino)-5,6,7,8-tetrahydroquinolin-2-yl)-2-methyl-1H-indole-7-carboxamideFF05

To a solution of 1H-indole-7-carbonitrile 1 (1.0 g, 7.04 mmol) in THF(30 mL) was added NaH (0.36 g, 9.15 mmol, 60%) at 0° C., and thereaction mixture was stirred at 20° C. for 30 min. Then benzenesulfonylchloride (1.49 g, 8.44 mmol) was added. The mixture was stirred at r.t,for 2 hours. The solution was quenched by adding a.q. NH₄Cl andextracted with EtOAc (300 mL×2), dried over Na₂SO₄ and concentratedunder vacuum. The residue was purified by flash chromatography(PE:EA=3:1) to afford 1-(phenylsulfonyl)-1H-indole-7-carbonitrile 2(1.83 g, 92%). LRMS (M+H⁺) m/z: calcd 282.32; found 282.

To a solution of 1-(phenylsulfonyl)-1 l-indole-7-carbonitrile 2 (1.83 g,6.49 mmol) in THF (30 mL) at −80° C. was added n-BuLi (3 mL, 7.14 mmol,2.4 N), the reaction mixture was stirred at −60° C. for 1 h. Theniodomethane (1.38 g, 9.73 mmol) was added. The reaction mixture wasstirred at ambient for 1 hour. The reaction was quenched by aq. NH₄Cland extracted with EA (200 mL×2), dried over Na₂SO₄ and concentratedunder vacuum. The residue was purified by flash chromatography(PE:EA=3:1) to afford2-methyl-1-(phenylsulfonyl)-1H-indole-7-carbonitrile 3 (1.83 g, 95%).LRMS (M+H⁺) m/z: calcd 296.34; found 296.

To a solution of 2-methyl-1-(phenylsulfonyl)-1H-indole-7-carbonitrile 3(1.6 g, 5.67 mmol) in DCM (15 mL) was added Br₂ (1.81 g, 11.34 mmol),the reaction mixture was stirred at ambient for 2 h. The reaction wasquenched by adding aq. NaHCO₃ and extracted with EA (60 ml×2), driedover Na₂SO₄ and concentrated under vacuum. The residue was purified byflash chromatography (PE:EA=3:1) to afford3-bromo-2-methyl-1-(phenylsulfonyl)-1H-indole-7-carbonitrile 4 (1.8 g,85%). LRMS (M+H⁺) m/z: calcd 375.24; found 375. ¹HNMR (300 MHz, CD₃OD):δ 7.66-7.84 (m, 5H), 7.46-7.58 (m, 3H), 2.66 (s, 3H).

To a solution of3-bromo-2-methyl-1-(phenylsulfonyl)-1H-indole-7-carbonitrile 4 (900 mg,2.4 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 5(450 mg, 2.4 mmol) in THF (15 mL) at −78° C. was added n-BuLi (1 mL, 2.4mmol, 2.4 N), and the reaction mixture was stirred at −78° C. for 1 h.Then the solution was allowed to warm to r.t, and stirred for 1 hour.The reaction was quenched by aq. NH₄Cl and extracted with EA (50 mL×2),dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by flash chromatography (PE:EA=2:1) to afford2-methyl-1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carbonitrile6 (760 mg, 75%). LRMS (M+H+) m/z: calcd 422.31; found 422. ¹HNMR (300MHz, CDCl₃): δ 8.28 (d, J=3.6 Hz, 1H), 7.97 (t. J=4.8 Hz, 2H), 7.60-7.63(m, 2H), 7.54 (t, J=5.4 Hz, 2H), 7.30 (t, J=7.8 Hz, 1H), 2.89 (s, 3H),1.37 (s, 12H). A mixture of2-methyl-1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carbonitrile6 (360 mg, 0.85 mmol),N-benzyl-2-chloro-5,6,7,8-tetrahydroquinazolin-4-amine 7 (232 mg, 0.85mmol), Pd(PPh₃)₄ (196 mg, 0.17 mmol) and Na₂CO₃ (176 mg, 1.7 mmol) indioxane (10 mL) and H₂O (3 mL) was heated at 100° (C for 16 hours undernitrogen atmosphere. The reaction mixture was cooled to room temperatureand concentrated under vacuum, The residue was purified by flashchromatography (PE:EA=1:1) to afford3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1-(phenylsulfonyl)-1H-indole-7-carbonitrile8 (217 mg, 48%). LRMS (M+H⁺) m/z: calcd 533.64; found 533.

To a solution of3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1-(phenylsulfonyl)-1H-indole-7-carbonitrile8 (120 mg, 0.22 mmol) in DMSO (5 mL) was added UHP (165 mg, 1.76 mmol).K₂C(O₃ (15 mg, 0.11 mmol) and water (0.3 mL) at 0° C., and the reactionmixture was stirred at 60° C. overnight. Water (100 mL) was added to themixture and the solid was crashed out, filtered to give the crudeproduct, which was purified by flash chromatography (DCM:MeOH=20:1) toafford3-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-7-carboxamide65 mg (72%) FF05. LRMS (M+H⁺) m/z: calcd 411.5; found 411. HPLC purity(214 nm): 97.6%. ¹HNMR (400 MHz, DMSO): δ 10.97 (s, 1H), 8.52 (d, J=4.0Hz, 1H), 8.00 (s, 1H), 7.57 (d, J=4.0 Hz, 1H), 7.27-7.35 (m, 5H), 7.18(t, J=7.2 Hz, 1H), 7.12 (t, J=6.0 Hz, 1H), 6.97 (t, J=8.0 Hz, 1H), 4.73(d, J=2.8 Hz, 2H), 2.70 (s, 3H), 2.66 (bs, 2H), 2.44 (bs, 2H), 1.81 (bs,4H).

Synthesis of1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideFF06

To a mixture of tetrahydropyran-2-one 1 (1.0 g, 10 mmol) andthiocyanatomethane (2.93 g, 40 mmol) in DCM (25 mL) was added Tf₂ ((4.23g, 15 mmol) in DCM (25 mL) dropwise at −78° C. under nitrogenatmosphere. After the addition, the resulting mixture was stirred at 0°C. for 3 h, and then stirred at mom temperature overnight. The volatilephase was removed off under reduced pressure. The residue was dissolvedin DCM (40 mL), washed with sodium bicarbonate, brine, dried over sodiumsulfate. The organic layer was concentrated under reduced pressure. Theresidue was applied onto silica gel column eluting with DCM. Thisresulted in 2,4-bis(methylthio)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine 2as white solid (0.4 g, 17.5%). LRMS (M+H⁺) m/z: calcd 229.0; found 229.

To a mixture of2,4-bis(methylthio)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine 2 (0.4 g,1.75 mmol) in DCM (20 mL) was added m-CPBA (2.47 g, 12 mmol)portionwise. The resulting mixture was stirred at room temperature for 5h. It was quenched with Na₂S₂O₃ (5%, 20 mL), then sat. NaHCO₃ (20 mL)was added carefully. The mixture was stirred for 30 min. The organiclayer was separated. The aqueous layer was extracted with DCM (20 mL×2).The organic layers were combined, washed with brine, dried over Na₂SO₄,filtered and concentrated. This resulted in 0.42 g (82%) of2,4-bis(methylsulfonyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine 3 inwhite solid. LRMS (M+H⁺) m/z: calcd 293.0; found 293.

A mixture of2,4-bis(methylsulfonyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine 3 (1.5 g,5.1 mmol) in 10% NaOH (30 mL) was refluxed for 2 h, then the reactionmixture was acidified with HCl (10%) until pH=2 and the solid wascollected by filtration, washed with H₂O. Recrystallization from H₂O togive 0.82 g (95.7%) 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-2,4-diol 4 inwhite solid. LRMS (M+H⁺) m/z: calcd 169.0; found 169.

A mixture of 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-2,4-diol 4 (0.4 g,2.4 mmol) in POCl₃ (10 mL) was stirred at 100° C. for 4 h. The volatilephase was removed off under reduced pressure. The residue was dissolvedin DCM (50 mL), and then was added ice/water, which was washed withNaHCO₃, brine, dried over sodium sulfate, filtered and concentrated. Theresidue was applied onto silica gel column eluting with PE/EA=4/1. Thisresulted in 0.25 g (50%) of2,4-dichloro-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine 5 as white solid.LRMS (M+H⁺) m/z: calcd 205.0; found 205.

A mixture of 2,4-dichloro-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine 5 (0.16g, 0.8 mmol) and Et₃N (0.24 g, 2.4 mmol) in DMF (15 mL) was stirred atroom temperature overnight. It was diluted with ethyl acetate (50 mL),which was washed with water, brine, dried over sodium sulfate, filteredand concentrated. The residue was applied onto silica gel column elutingwith PE /EA=21. This resulted in 0.16 g (74.5%) ofN-benzyl-2-chloro-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-amine 6 aswhite solid. LRMS (M+H⁺) m/z: calcd 276.1; found 276.

To a mixture ofN-benzyl-2-chloro-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-amine 6 (82mg, 0.3 mmol), 2-methyl-1H-indole-4-carbonitrile 7 (48 mg, 0.3 mmol),Pda₂(dba)₃ (55 mg, 0.06 mmol), X-Phos (57 mg, 0.12 mmol) and Cs₂CO₁ (196mg, 0.6 mmol) in dioxane (8 ml) was stirred at 100° C. overnight. Thevolatile phase was removed off under reduced pressure. The residue wasapplied onto silica gel column eluting with PE/EA=2/1. This resulted in80 mg (68%) of1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbonitrile8 as a yellow solid. LRMS (M+H⁺) mm/z: calcd 396.2: found 396.

A mixture of1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbonitrile8 (72 mg, 0.182 mmol), 1-hydroperoxyurea (112 rig, 1.45 mmol) and K₂CO₃(13 mg, 0.09 mmol) in DMSO/H₂O (10 mL/1 mL) was stirred at roomtemperature for 3 h. It was diluted with 50 mL water, which wasextracted with ethyl acetate (20 mL×3).

The organic layers were combined, washed with brine, dried over sodiumsulfated, filtered and concentrated. The residue was applied onto silicagel column eluting with PE/EA=2/1. This resulted in 50 mg (66%) of1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideFF06 as yellow solid. LRMS (M+^(H)) m/z: calcd 414.2; found 414. HPLCpurity (214 nm): 97%. ¹HNMR (400 MHz, DMSO): δ 7.88 (d, J=8.0 Hz, 1H),7.75-7.71 (m, 1H), 7.69-7.7.65 (m, 1H), 7.45 (d, J=8.0 Hz, 1H),7.40-7.30 (m, 4H), 7.28-7.20 (m, 2H), 6.94 (t. J=8.0 Hz, 1H), 4.69 (d,J=8.0 Hz, 2H), 4.31 (t, J=4.0 Hz, 2H), 2.52-2.50 (m, 2H), 2.48 (s, 3H),2.06-2.02 (m, 3H).

Synthesis of1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideFF07

To a solution of pyrido[2,3-d]pyrimidine-2,4-diol 1 (0.80 g, 4.9 mmol)in AcOH/H₂O (12 mL/8 mL) was added Pd(OH)₂ (0.08 g, 0.57 mmol). Themixture was heated at 70° C. overnight under hydrogen atmosphere. Themixture was filtered to afford5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4-diol 2 (0.5 g, 61%). LRMS(M+H⁺) m/z: calcd 168.07; found 168.

A mixture of 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4-diol 2 (500mg, 2.99 mmol) and PCl₅ (300 mg, 1.5 mmol) in POCl₃ (10 mL) was heatedat 130° C. overnight. The reaction mixture was cooled to roomtemperature and concentrated under vacuum, the residue was dissolved inDCM (20 mL) and poured into ice water (20 mL), the oil layer wasconcentrated under vacuum and the residue was purified by flashchromatography (petroleum:ethyl acetate=5:1) to afford2,4-dichloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 3 (150 mg, 25%).LCMS (M+H⁺) m/z: calcd 204.00; found 203.9.

A mixture of 2,4-dichloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 3(150 mg, 0.74 mmol), DMAP (91 mg, 0.74 mmol) and Boc₂O (241 mg, 1.1mmol) in CH₃CN (10 mL) was stirred at room temperature for 0.5 hour. Thereaction mixture was concentrated under vacuum, and the residue waspurified by flash chromatography (petroleum:ethyl acetate=10:1) toafford tert-butyl2,4-dichloro-6,7-dihydropyrido[2,3-d]pyrimidine-8(5H)-carboxylate 4 (100mg, 45%). LRMS (M+H) m/z: calcd 248.05; found 247.9.

To a solution of tert-butyl2,4-dichloro-6,7-dihydropyrido[2,3-d]pyrimidine-8(5H)-carboxylate 4 (100mg, 0.33 mmol) and TEA (100 mg, 0.99 mmol) in CH₃CN (10 mL) was addedphenylmethanamine (43 mg, 0.39 mmol) stirred at 70° C. overnight. Thereaction mixture was cooled to room temperature and concentrated undervacuum, the residue was purified by flash chromatography(petroleum/ethyl acetate) to afford tert-butyl4-(benzylamino)-2-chloro-6,7-dihydropyrido[2,3-d]pyrimidine-8(5H)-carboxylate5 (100 mg, 81%). LRMS (M+H⁺) m/z: calcd 375.15; found 375.1.

A mixture of tert-butyl4-(benzylamino)-2-chloro-6,7-dihydropyrido[2,3-d]pyrimidine-8(5H)-carboxylate5 (100 mg, 0.27 mmol), 2-methyl-1H-indole-4-carbonitrile 6 (41 mg, 0.32mmol), tris(dibenzylideneacetone) dipalladium (98 mg, 0.11 mmol). X-phos(26 mg, 0.05 mmol) and Cs₂CO₃ (174 mg, 0.54 mmol) in dioxane (10 mL) washeated at 100° C. for 3 hours under nitrogen atmosphere.

The reaction mixture was cooled to room temperature and concentratedunder vacuum, and the residue was purified by flash chromatography(petroleum/ethyl acetate) to afford tert-butyl4-(benzylamino)-2-(4-cyano-2-methyl-1H-indol-1-yl)-6,7-dihydropyrido[2,3-d]pyrimidine-8(5H)-carboxylate7 (80 mg, 61%). LCMS (M+^(H)+) m/z: calcd 495.24; found 495.2.

To a solution of tert-butyl4-(benzylamino)-2-(4-cyano-2-methyl-1H-indol-1-yl)-6,7-dihydropyrido[2,3-d]pyrimidine-8(5H)-carboxylate7 (80 mg, 0.16 mmol) in DMSO (8 mL) was added UHP (123 mg, 1.29 mmol)and K₂CO₃ (12 mg, 0.081 mmol), added water (0.5 mL) and the reaction wasstirred at room temperature for 2 hours. Water (100 mL) was added to themixture and the solid formed was filtered to afford tert-butyl4-(benzylamino)-2-(4-carbamoyl-2-methyl-1H-indol-1-yl)-6,7-dihydropyrido[2,3-d]pyrimidine-8(5H)-carboxylate8 (60 m, 70%). LCMS (M+H⁺) m/z: calcd 513.25; found 513.

To a solution of tert-butyl4-(benzylamino)-2-(4-carbamoyl-2-methyl-1H-indol-1-yl)-6,7-dihydropyrido[2,3-d]pyrimidine-8(5H)-carboxylate8 (60 mg, 0.12 mmol) in EtOAc (2 mL) was added HCl/EA (5 mL, 2 N), thenstirred at room temperature for 1 hour. The solid formed was filtered toafford1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideFF07 as a white solid (20 mg, 40%). LCMS (M+H⁺) m/z: calcd 413.2; found413.1. HPLC purity (214 nm): 100%. ¹HNMR (400 MHz. DMSO): δ 7.79-7.65(m, 2H), 7.50-7.41 (m, 2H), 7.38-7.19 (m, 7H), 6.97-6.89 (m, 1H),6.88-6.79 (m, 1H), 4.62-4.59 (m, 2H), 3.33-3.26 (m, 2H), 2.54-2.52 (m,2H), 2.45 (s, 3H), 1.94-1.86 (m, 2H).

Synthesis of1-[4-(Benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl]-2-methyl-indole-4-carboxamideFF06

To a solution of EtOH (400 mL) was added Na (2.66 g, 0.12 mol) inportions. After all the sodium was dissolved, triethylethane-1,1,2-tricarboxylate (19 g, 77.16 mmol) and urea (5.1 g, 84.87mmol) were added to the reaction successively. The white suspension wasrefluxed for 16 h. A lot of white solid formed. TLC showed the reactionwas completed. The reaction mixture was filtered and the filter cake waswashed with EtOH (200 mL). The filtrate was concentrated in vacuo togive the desired Ethyl 2-(2,4,6-trioxohexahydropyrimidin-5-yl)acetate(15 g, 81.7%) as a white solid which was confirmed at next step. LCMS(M−H⁺) m/z: Calcd: 213.05; Found: 213.3.

A white suspension of ethyl2-(2,4,6-trioxohexahydropyrimidin-5-yl)acetate (19 g, 88.71 mmol) inPOCl₃ (100 mL) was refluxed for 16 h. The color of reaction mixtureturned to brown. TLC showed the reaction was completed. The reactionmixture was concentrated in vacuo. The brown residue was purified bycolumn chromatography on silica gel (PE:EA=20:1 to 5:1) to give thedesired Ethyl 2-(2,4,6-trichloropyrimidin-5-yl)acetate (1.8 g, 6.8%) asbrown oil. LCMS (M+II) m/z: Calcd: 268.97; Found: 269.0.

To a solution of ethyl 2-(2,4,6-trichloropyrimidin-5-yl)acetate (500 mg,1.86 mmol) in THF (20 mL) was added DIBAL-H (1 M in toluene, 7.42 mL)drop wise at 0° C. The light yellow solution was stirred at 15° C. for12 h. TLC showed the reaction was completed. The reaction was quenchedby 1 N HCl (20 mL.). The resulting mixture was extracted with EA (20mL*3). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (PE:EA=10:1 to 1:1) to give the desired2-(2,4,6-Trichloropyrimidin-5-yl)ethanol (0.2 g, 42.7%) as brown solid.LCMS (M+H⁺) m/z: Calcd: 226.95; Found: 227.0.

To a colorless solution of 2-(2,4,6-trichloropyrimidin-5-yl)ethanol (500mg, 2.2 mmol) in anhydrous THF (50 mL) was added NaH (131.87 mg, 3.3mmol, 60% in mineral oil) at r.t. The reaction mixture was stirred atr.t, for overnight. TIC showed the reaction was completed. The reactionwas quenched by adding sat. NH₄Cl (20 mL) and then extracted with EA (20ml.*3). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The residual was purified by prep-TLC to give thedesired 2,4-Dichloro-5,6-dihydrofuro[2,3-d]pyrimidine (0.1 g, 21.4%) asa white solid. LCMS (M+H⁺) m/z: Calcd: 190.97; Found: 191.1.

A colorless solution of 2,4-dichloro-5,6-dihydrofuro[2,3-d]pyrimidine(90 mg, 0.47 mmol), phenylmethanamine (55.54 mg, 0.52 mmol) and TEA(57.21 mg, 0.57 mmol) in MeCN (25 mL) was refluxed for 16 h. LCMS showedthe reaction was completed. The reaction mixture was concentrated invacuo and purified by prep-TLC (PE:EA=1:1) to give the desiredN-Benzyl-2-chloro-5,6-dihydrofuro[2,3-d]pyrimidin-4-amine (50 mg, 36.5%)as a white solid. ¹HNMR (400 MHz, CDCl₃): δ 7.30 (m, 5H, Ph), 5.50 (s,1H, NH), 4.63 (m, 4H, NHCH ₂. OCH ₂), 3.18 (m, 2H, PhCH ₂). LRMS (M+H⁺)m/z: Calcd: 262.07; Found: 262.1 A red suspension ofN-benzyl-2-chloro-5,6-dihydrofuro[2,3-d]pyrimidin-4-amine (45 mg, 0.17mmol), 2-methyl-1H-indole-4-carbonitrile (32.23 mg, 0.21 mmol),Pd₂(dba)₃ (31.49 mg, 0.03 mmol), K₂CO₃ (47.53 rag, 0.34 mmol) and X-Phos(16.39 mg, 0.03 mmol) in dioxane (5 mL) was refluxed for 2 h under N₂.LCMS showed the reaction was completed. The reaction was filtered andthe filtrate was concentrated in vacuo. The crude product was purifiedby prep-TLC (PE:EA=5:1) to give the desired1-[4-(Benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl]-2-methyl-indole-4-carbonitrile(50 mg, 68.6%) as light yellow solid. LRMS (M+H⁺) m/z: Calcd: 382.16;Found: 382.2.

A light yellow solution of1-[4-(benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl]-2-methyl-indole-4-carbonitrile(45 mg, 0.12 mmol), UHP (55.49 mg, 0.59 mmol) and K₂CO₃ (16.31 mg, 0.12mmol) in DMSO (20 mL) and H₂O (1 mL) was stirred at 15° C. for 2 h. TLCshowed the reaction was completed. EA (20 mL) and brine (20 mL) wasadded to the reaction. The organic layer was separated and washed withbrine (20 mL*3), dried over Na₂SO₄ and concentrated in vacuo. The yellowresidue was purified by prep-TLC to give the desired1-[4-(Benzylamino)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl]-2-methyl-indole-4-carboxamideFF08 (30 mg, 63.7%) as a white solid. ¹HNMR (400 MHz. CDCl₃): δ 8.28 (d,1H, {right arrow over (Ph)}), 7.49 (d, 1H, PH), 7.43-7.30 (m, 5H, CH₂Ph), 7.10 (m, 1H, {right arrow over (Ph)}), 6.83 (s, 1H, 3-H of indole),6.15 (s, 2H, NH ₂), 4.98 (s, 1H, NH), 4.81-4.61 (m, 4H, OCH ₂+NHCH ₂),3.08 (m, 2H, CH ₂), 2.74-2.57 (s, 3H, CH ₃). LRMS (M+H⁺) m/z: Calcd:400.18; Found: 400.2.

Synthesis of1-(4-((3-Fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideFF09

To a mixture of 2,4-dichloro-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine (250mg, 1 mmol) in ACN (20 mL) was added DIPEA (464 mg, 4 mmol) compound 2(604 mg, 5 mmol). The reaction mixture was refluxed for 16 h. TLC(PE:EA=2:1) show the reaction was completed. Then the mixture wasconcentrated and purified by silica gel (PE:EA=6:1 to 3:1) to give thedesired2-chloro-N-(3-fluorobenzyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-amine(240 mg, 67.67%) as a white solid. LCMS (M+H⁺) m/z: Calcd: 294.07;Found: 294.1.

To a solution of2-chloro-N-(3-fluorobenzyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-anine(820 mg, 3 mmol) in dioxane (150 mL) were added2-methyl-1H-indole-4-carbonitrile (654 mg, 4 mmol), Cs₂CO₃ (1.819 g, 6mmol), X-Phos (532 mg, 1 mmol) and Pd₂(dba)₃ (767 mg, 0.838 mmol). Theresulting mixture was stirred at 100° C. for 12 h under N₂. TLC(PE:EA=1:1) show the reaction was completed. Then the mixture wasfiltered, the filtrate was concentrated and purified by silica gel(PE:EA=10:1) to give the desired1-(4-((3-Fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbonitrile(600 mg, 52%). LCMS (M+H⁺) m/z: Calcd: 414.17; Found: 414.2.

To a mixture of1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbonitrile(0.6 g, 1 mmol) in DMSO (50 mL) was added UHP (0.697 g, 7 mmol) andK₂CO₃ (0.1 g, 0.726 mmol). The reaction mixture was stirred for 10 min.Then H₂O (5 mL) was added and stirred for 12 h at 25° C. TLC (PE:EA=1:2)show the reaction was completed. Then H₂O (500 mL) was added, and thenextracted with EA (200 mL*3). The combined organic phase wasconcentrated and purified by silica gel (PE:EA=5:1 to 1:1) to give crudeproduct which was washed with ACN (10 mL), filtered and concentrated togive the desired1-(4-((3-Fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideFF09 (0.2 g, 31.3%). LCMS (M+H⁺) m/z: Calcd: 432.18; Found: 432.2. ¹HNMR(400 MHz, CD₃OD): δ 7.73 (d, J=8.4 Hz, 1H, Ph), 7.47 (d, J=7.2 Hz, 1H,Ph), 7.34 (m, 1H, Ph), 7.16-7.14 (d, J=7.2 Hz, 1H, Ph), 7.04 (m, 1H,Ph), 7.00-6.97 (m, 2H, Ph), 6.77 (s, 1H, 3-H of indole), 4.73 (s, 2H,PhCH ₂NH), 4.40-4.38 (m, 2H, OCH ₂CH₂CH₂), 2.61-2.58 (m, 2H, OCH₂ CH₂CH₂), 2.46 (s, 3H, NCCH ₃), 2.17-2.14 (m, 2H, OCH₂CH₂ CH ₂).

Synthesis of3-[4-(Benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl-2-methyl-1H-indole-7-carboxamideFF10

To a solution of 2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (1g, 4.877 mmol) in ACN (50 nil) was added BnNH₂ (0.78 g, 7.316 mmol). Themixture was stirred at 25° C. for 12 h under N₂. TLC showed the reactionwas completed. The reaction was concentrated in vacuo and purified bycolumn chromatography (PE/EA=10/1 to 5/1) to give the desiredN-Benzyl-2-chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (0.85 g,60.5% yield) as a white solid.

To a solution ofN-benzyl-2-chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (300 mg,1.09 mmol) and1-(benzenesulfonyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-7-carbonitrile(551 mg, 1.31 mmol) in dioxane (10 mL) and H₂O (2 mL) were added KCO₃(300 mg, 2.17 mmol) and Pd(PPh₃)₄ (126 mg, 0.11 mmol). The mixture wasstirred at 100° C. under N₂ for 3 h. TLC showed the reaction wascompleted. The mixture was diluted with IA (20 ml) and H₂O (5 mL). Theorganic phase was separated, dried over Na₂SO₄, concentrated andpurified by column chromatography (PE:EA=10:1 to pure EA) to afford thedesired1-(Benzenesulfonyl)-3-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-indole-7-carbonitrile(300) mg, 50.5%) as a white solid. LCMS (M+H⁺), m/z: Calcd: 536.17;Found: 536.2.

To a solution of1-(benzenesulfonyl)-3-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-indole-7-carbonitrile(150 mg, 280 mmol) in DMSO (10 mL) and H₂O (0.2 mL) were added UHP (130mg, 1.4 mmol) and K₂C)₃ (19 mg, 140 mmol). The mixture was stirred at60° C. for 12 h. TLC showed 10%1-(benzenesulfonyl)-3-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-indole-7-carbonitrilewas remained. The mixture was poured into H₂O (100 mL) and thenextracted with EA (50 mL*2).

The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, concentrated in vacuo to dryness and purified by columnchromatography (PE:EA=5:1 to 100% EA) to afford the desired3-[4-(Benzylamnino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl-2-methyl-1H-indole-7-carboxamideFF10 (60 ing, 50.3%). LCMS (M+H⁺) m/z: Calcd: 414.19; Found: 414.3.¹HNMR (400 MHz, CDCl₃): δ 11.05 (s, 1H, CONH ₂), 8.53 (d, J=8.0 Hz, 1H,C₆ H ₃), 8.02 (s, 1H, CONH ₂), 7.57-7.59 (m, 1H, C₆ H ₃), 7.31-7.35 (m,5H, C₆ H ₃), 7.20-7.21 (m, 1H, C₆ H ₃), 7.14-7.15 (m, 1H, NH), 6.99-7.02(m, 1H, NH), 4.72-4.73 (d, J=7.2 Hz, 2H, CH ₂), 4.55 (s, 2H, CH ₂), 3.96(t, J=5.6 Hz, CH ₃), 2.72-2.73 (m, 5H, CH ₂, CH ₃)

Synthesis of1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamideFF11

A mixture of 3-aminopicolinic acid (5.00 g, 36.2 mmol) and urea (10.9 g,181 mmol) in a 100 mL flask was stirred at 170° C. for 6 h. The reactionmixture was turned from clear solution to suspension. Then the reactionmixture was cooled to 25° C., and filtered. The filter cake was washedwith water (50 mL) and dried to give the desiredPyrido[3,2-d]pyrimidine-2,4-diol (3.2 g, 74.5%) as a white solid. ¹HNMR(400 MHz, CDCl₃): δ 11.66 (s, 1H, OH), 11.16 (s, 1H, OH), 8.59 (d,0.1=2.4 Hz, 1H, C₆ H ₃), 8.25 (d, J=8.4 Hz, 1H, C₆ H ₃), 7.24 (t, J=2.4Hz, 1H, C₆ H ₃).

A mixture of pyrido[3,2-d]pyrimidine-2,4-diol (5.0 g, 0.031 mol), POCl₃(150 mL) and PCl₅ (25.5 g, 0.128 mol) was stirred at 130° C. for 3 h.TLC showed the reaction was completed. It was concentrated in vacuo, theresidue was dissolved with DCM (1000 mL) and then poured into H₂O (400mL). The organic layer was separated, washed with sat. Na₂CO₃ (400 mL),dried with Na₂SO₄, filtered, concentrated in vacuo and purified bycolumn chromatography (PE:EA=10:1 to PE:EA=3:1) to afford pure desired2,4-dichloropyrido[3,2-d]pyrimidine (3.5 g, 57.4%) as a yellow solid.¹HNMR (400 MHz, CDCl₃): 9.33 (t, J=2.4 Hz, 1H, C₆ H ₃), 8.64 (d, J=7.6Hz, 1H, C₆ H ₃), 7.71-7.75 (m, 1H, C₆ H ₃).

To a yellow solution of 2,4-dichloropyrido[3,2-d]pyrimidine (500 mg, 2.5mmol) in anhydrous THF (30 mil) were added (3-fluorophenyl)methanamine(344 mg, 2.75 mmol) and TEA (379 mg, 3.75 mmol). Then the mixture wasstirred at 60° C. for 1 h under N₂. TLC showed the reaction wascompleted. The reaction mixture was concentrated to dryness in vacuo toafford crude2-Chloro-N-[(3-fluorophenyl)methyl]pyrido[3,2-d]pyrimidin-4-amine (0.72g, 84.8%) as a yellow solid.

To a yellow suspension of2-chloro-N-[(3-fluorophenyl)methyl]pyrido[3,2-d]pyrimidin-4-amine (0.72g, 2.5 mmol) in EtOH (50 nil) was added PtO₂ (110 mg). Then the mixturewas stirred at 60° C. under H₂ (15 psi) over 6 h. TLC showed the ratioof product:2-chloro-N-[(3-fluorophenyl)methyl]pyrido[3,2-d]pyrimidin-4-amine=1:1.Catalyst was removed by filtration. The filtrate was concentrated todryness in vacuo and purified by column chromatography (PE:EA=5:1 to1:1) to afford the desired2-chloro-N-[(3-fluorophenyl)methyl]-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine(300 mg, 37%) as a white solid.

To a white suspension of2-chloro-N-[(3-fluorophenyl)methyl]-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine(250 mg, 0.854 mmol) in anhydrous THF (10 mL) was added paraformaldehyde(153.85 mg, 1.708 mmol) and one drop AcOH. Then the white suspension wasstirred at 20° C. for 3 h. NaBH(OAc)₃ (362 mg, 1.708 mmol) was added tothe above mixture. Then the mixture was stirred at 80° (C for 9 h. LCMSand TLC showed2-chloro-N-[(3-fluorophenyl)methyl]-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine:Product=1:2.The white suspension was filtered through celitic and the filtrate wasconcentrated to dryness in vacuo and purified by column chromatography(PE:EA=10:1 to 1:1) to afford the desired2-chloro-N-[(3-fluorophenyl)methyl]-5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-4-amine(200 mg, 57%) as colorless oil. LCMS (M+H⁺) m/z: Calcd: 307.11; Found:307.10. ¹HNMR (400 MHz, CDCl₃): δ 7.32 (t, J=6.0 Hz, 1H, C₆ H ₃), 7.13(d, J=7.6 Hz, 1H, C₆ H ₄), 7.06-7.00 (m, 2H, C₆ H ₄), 5.67 (s, 1H, NH),4.69 (d. J=7.2 Hz, 2H, CH ₂Ph), 2.96-3.02 (m, 2H, CH ₂), 2.71-2.74 (m,2H, CH ₂), 2.58 (s, 3H, CH ₃), 1.95-1.99 (m, 2H, CH ₂).

To a solution of2-chloro-N-[(3-fluorophenyl)methyl]5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-4-amine(50 mg, 0.16 mmol) and 1H-indazole-4-carbonitrile (25.66 mg, 0.18 mmol)in anhydrous dioxane (10 mL) were added X-Phos (15.52 mg, 0.033 mmol),Pd₂dba₃ (29.83 mg, 0.033 mmol) and Cs₂CO₃ (106.92 mg, 0.326 mmol). Thenthe mixture was stirred at 100° C. for 12 under N₂. TLC showed Product:2-chloro-N-[(3-fluorophenyl)methyl]-5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-4-amine=1:1.The mixture was filtered through celitic, concentrated to dryness invacuo and purified by column chromatography (PE:EA=10:1 to 1:1) toafford the desired1-[4-[(3-Fluorophenyl)methylamino]-5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-2-yl]indazole-4-carbonitrile(20 mg, 23.7%) as yellow oil. LCMS (M+H⁺) m/z: Calcd: 414.18; Found:414.2.

To a yellow solution of1-[4-[(3-fluorophenyl)methylamino]-5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-2-yl]indazole-4-carbonitrile(20 mg, 0.05 mmol) in DMSO (3 mL) and H₂O (0.3 mL) were added UHP (22.74mg, 0.242 mmol) and K₂CO₃ (3.338 mg, 0.024 mmol). Then the mixture wasstirred at 20° C. for 2 h. TLC showed the reaction was completed. To theabove mixture were added H₂O (30 ml) and EA (20 mL). The organic phasewas separated and the aqueous layer was extracted with EA (10 mL*2). Thecombined organic layers were washed with brine (15 mL*5), dried overNa₂SO₄, concentrated to dryness in vacuo and purified by prep-TLC(EA:MeOH=3:1) to afford the desired1-[4-[(3-Fluorophenyl)methylamino]-5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-2-yl]indazole-4-carboxamideFF11 (6 mg, 26.4%) as a white solid. LCMS (M+H) m/z: Calcd: 432.19;Found: 432.3. ¹HNMR (400 MHz, CDCl₃): δ 8.73 (s, 1H, CH), 8.55 (d, J=8.0Hz, 1 Hz, C₆ H ₄), 7.34-7.54 (m, 3H, C₆ H ₄), 7.01-7.22 (m, 3H, C₆ H ₃),6.12 (s, 2H, CONH ₂), 5.86 (s, 1H, NH), 3.10 (m, CH ₂), 2.93 (m, CH ₂),2.69 (s, CH ₃), 1.62 (s, CH ₂).

Synthesis of1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideFF12

To a solution of2-chloro-N-[(3-fluorophenyl)methyl]-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine(500 mg, 1.71 mmol) in anhydrous THF (50 mL) were added (HCHO)_(m) (923mg, 10.27 mmol) and AcOH (5 drops). Then the mixture was stirred at 25°C. with a drying tube for 8 h. Then NaBH₃CN (644 mg, 10.27 mmol) wasadded. The mixture was stirred at 80° C. for further 48 h. The mixturewas quenched with H₂O (20 mL) and then extracted with EA (50 mL*3). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, concentrated to dryness in vacuo and purified by columnchromatography (PE:RA=10:1 to 5:1) to afford the desired2-Chloro-N-[(3-fluorophenyl)methyl]-5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-4-amine(340 mg, 60.3%) as red oil. LCMS (M+H⁺) m/z: Calcd: 307.11; Found:307.10. ¹HNMR (400 MHz, CDCl₃): δ 7.32 (t, J=6.0 Hz, 1H, C₆ H ₄), 7.13(d, J=7.6 Hz, 1H, C₆ H ₄), 7.06-7.00 (m, 2H, C₆ H ₄), 5.62 (s, 1H, NH),4.69 (d, J=7.2 Hz, 2H, CH ₂Ph), 2.96-3.02 (m, 2H, CH ₂), 2.71-2.74 (m,2H, CH ₂), 2.58 (s, 3H, CH ₃), 1.93-1.99 (nm, 2H, CH2).

To a suspension of2-chloro-N-[(3-fluorophenyl)methyl]-5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-4-amine(100 mg, 0.326 mmol) and 2-methyl-1H-indole-4-carbonitrile (61 mg, 0.392mmol) in dioxane (10 mL) were added Pd₂(dba)₃ (60 mg, 0.065 mmol),X-Phos (31 mg, 0.065 mmol) and Cs₂CO₃ (214 mg, 0.978 mmol). Then themixture was stirred at 100° C. for 12 h under N₂. LCMS showedproduct:by-product (298)=4:1. The mixture was diluted with H₂O (10 mL)and then extracted with EA (10 mL*3). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, concentrated to dryness invacuo and purified by prep-HPLC (TFA) to afford the desired1-[4-[(3-fluorophenyl)methylamino]-5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-2-yl]-2-methyl-indole-4-carbonitrile(100 mg, 68.3%) as a white solid. LCMS (M+H⁺) m/z: Calcd: 427.20; Found:427.1.

To a solution of1-[4-[(3-fluorophenyl)methylamino]-5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-2-yl]-2-methyl-indole-4-carbonitrile(90 mg, 0.211 mmol) in DMSO (10 mL) and H₂O (1 mL) were added UHP (99mg, 1.055 mmol) and K₂CO₃ (15 mg, 0.105 mmol). The mixture was stirredat 20° C. for 4 h. TLC showed the reaction was completed. The mixturewas quenched with H₂O (20 mL) and then extracted with EA (10 mL*3). Thecombined organic layers were washed with brine (10 mL*5), dried overNa₂SO₄, concentrated to dryness in vacuo and purified by prep-TLC(PE:EA=1:3) to afford the desired1-[4-[(3-fluorophenyl)methylamino]-5-methyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-2-yl]-2-methyl-indole-4-carboxamideFF12 (30 mg, 33.8%) as a white solid. LCMS (M+H⁺) m/z: Calcd: 445.22;Found: 445.3. ¹HNMR (400 MHz, CDCl₃): δ 8.06 (d, J=8.0 Hz, 1H, C₆ H ₃),7.51 (d, J=7.2 Hz, 1H, C₆ H ₃), 7.28-7.33 (m, 1H, C₆ H ₃), 7.00-7.14 (m,4H, C₆ H ₄), 6.80 (s, 1H, CH ₃), 6.08 (s, 2H, CONH ₂), 5.77 (s, 1H, NH),4.74 (d, J=6.0 Hz, 2H, PhCH ₂), 3.08-3.12 (m, 2H, CH ₂), 2.81-2.86 (m,CH ₂), 2.71 (s, 3H, CH ₃), 2.59 (s, 3H, CH₃), 2.04-2.06 (m, 2H, CH ₂).

Synthesis of1-(4-(benzylamino)-6,8-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideFF13

A solution of BnNH₂ (50.0 g, 0.47 mol) and methyl methacrylate (56.04 g,0.560 mol) in MeOH (1000 mL) was stirred for 5 h at 25° C. under N₂. TLCshowed 70% SM was remained. Then the solution was heated to reflux andstirred for overnight. TLC showed the reaction was completed. Then thesolution was concentrated in vacuum to give methyl3-(benzylamino)-2-methylpropanoate 2 (60 g, 62%) as pink oil.

A solution of compound 2 (60.0 g, 0.29 mol) and methyl acrylate (30.0 g,0.35 mol) in MeOH (800 mL) was heated to reflux and stirred forovernight. TLC showed the reaction was completed. Then the solution wasconcentrated in vacuum to give crude product of methyl3-(benzyl(3-methoxy-3-oxopropyl)amino)-2-methylpropanoate 3 (70 g, about80% purity) as pink oil.

To a solution of compound 3 (20 g, 68.18 mol) in toluene (300 ml). NaH(3.272 g, 81.81 mmol) was added slowly. The mixture was stirred at 90°C. for 12 h under N₂. TLC showed the reaction was completed. After beingcooled, the reaction solution was quenched with 100 mL of water, thenextracted with EA (200 mL*2). The combined organic phase wasconcentrated in vacuum and purified by silica gel column chromatography(PE:EA=50:1 to 25:1) to give methyl1-benzyl-5-methyl-4-oxopiperidine-3-carboxylate 4 (13.6 g, 76.4%) ascolorless oil. LCMS (M+H) m/z: Calcd: 262.14; Found: 262.2.

To a solution of compound 4 (15 g, 0.06 mol) in MeOH (200 mL), urea(6.89 g, 0.11 mol) and NaOMe (15.51 g, 0.29 mol) were added slowly. Themixture was stirred at 70° C. for 16 h under N₂. TLC showed the reactionwas completed. Then the mixture was cooled to r.t, and then filtered.The filter cake was washed with EtOH (100 mL*2) and dried in vacuum togive the product of6-benzyl-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione5 (6.3 g, 40%) as a white solid. LCMS (M+WI) m/z: Calcd: 272.14; Found:272.10.

A solution of compound 5 (3.0 g, 0.011 mol) in POCl₃ (100 mL) wasstirred at 120° C. for 4 h. LCMS showed the reaction was completed; themixture was concentrated in vacuum to give a residue. It was dilutedwith EA (200 mL) and poured into H₂O (50 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated to give crudecompound 6 which was suspended in MTBE (50 mL) and filtered to give pure6-Benzyl-2,4-dichloro-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine6 (2.0 g, 54.58%) as a yellow solid. LCMS (M+H⁺) m/z: Calcd: 308.06;Found: 308.1.

To a solution of compound 6 (4.1 g, 0.013 mol) in DCE (150 mL) at 25° C.under N₂ was added 1-chloroethyl carbonochloridate (38.04 g, 0.266 mol).The mixture was refluxed for 48 h. LCMS showed the reaction wascompleted: it was concentrated to dryness and dissolved in anhydrousMeOH (150 mL) and stirred at 25° C. for 12 h. LCMS showed the reactionwas completed, it was concentrated to dryness in vacuum to afford crudeproduct. It was suspended in EA (5 mL) and filtered to give pure2,4-dichloro-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine 7 (2.0g, 68%) as a yellow solid. LCMS (M+H⁺) m/z: Calcd: 218.02; Found: 218.1.

A mixture of compound 7 (2.0 g, 9.171 mmol), Boc₂O (2.999 g, 13.76 mmol)and Et₃N (1.853 g, 18.34 mmol) in DCM (120 mL) was stirred at 25° C. for3 h. TLC and LCMS showed the reaction was completed. The reactionmixture was concentrated to give a residue, which was suspended in MTBE(20 mL) and filtered to give pure tert-Butyl2,4-dichloro-8-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate8 (2.1 g, 72%) as a yellow solid. LCMS (M+H+) m/z: Calcd: 318.02; Found:318.1.

To a solution of compound 8 (1.9 g, 5.971 mmol) and TEA (1.206 g, 11.94mmol) in ACN (50 mL) was added BnNH₂ (0.768 g, 7.165 mmol). The mixturewas stirred at 85° C. for 3.5 h. TLC and LCMS showed the reaction wascompleted, it was concentrated in vacuum to get a residue, which waspurified by column chromatography (PE/EA=10/1 to 5/1) to give tert-butyl4-(benzylamino)-2-chloro-8-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate9 (1.9 g, 82%) as a yellow solid. LCMS (M+H⁺) m/z: Calcd: 389.17; Found:389.2.

A mixture of compound 9 (389 mg, 1 mmol), 2-methyl-4-nitrile-indole(0.203 g, 1.3 mmol), Pd₂(dba)₃ (0.275 g, 0.3 mmol), X-Phos (0.187 g, 0.4mmol) and Cs₂CO₃ (0.652 g, 2 mmol) in dioxane (50 mL) was stirred at100° C. for 2 h under N₂. TLC showed the reaction was completed. It wasconcentrated to get a residue, which was purified by columnchromatography (PE/EA=5/1) to give tert-butyl4-(benzylamino)-2-(4-cyano-2-methyl-1H-indol-1-yl)-8-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate10 (0.34 g, 67%) as a yellow solid. LCMS (M+H⁺) m/z: Calcd: 509.27;Found: 509.3.

A solution of compound 10 (0.28 g, 0.551 mmol) in TFA (20 mL, 20% inDCM) was stirred at 25° C. for 12 h. LCMS showed the reaction wascompleted, it was poured into sat. NaHCO₃ (250 mL) and extracted with EA(100 mL*2). The combined organic phase was dried over Na₂SO₄, filteredand concentrated to give1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbonitrile12 (0.13 g, 60%) as a yellow solid. LCMS (M+H⁺) nd/z Calcd: 409.21;Found: 409.3.

A mixture of compound 12 (110 mg, 0.269 mmol), (CH₂O)n (72.71 mg, 0.808mmol) and three drops of AcOH in THF (40 mL) was stirred at 25° C. for 3h, then NaBH₃(AcO)₃ (171.26 mg, 0.808 mmol) was added to the mixture.The reaction was stirred at 90° C. for 12 h. LCMS showed the reactionwas completed, it was concentrated in vacuum to get a residue, which waspurified by prep-TLC to give1-(4-(benzylamino)-6,8-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbonitrile13 (0.095 g, 83.5%) as a yellow solid. LCMS (M+H⁺) m/z Calcd: 423.23;Found: 423.3.

A mixture of compound 13 (95 mg, 0.098 mmol), UHP (0.106 g, 0.001 mol)and K₂CO₃ (0.031 g, 0.225 mmol) in DMSO/H₂O (6.0 ml, V/V, 10/1) wasstirred at 25° C. for 12 h. LCMS showed the reaction was completed. Itwas poured into H₂O (15 mL) and extracted with EA (25 mL*2). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedto get a residue. It was purified by prep-TLC to give1-(4-(Benzylamino)-6,8-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideFF13 (35 mg, 35.3%) as a yellow solid. LCMS (M+H⁺) m/z: Calcd: 441.2;Found: 441.3. ¹HNMR (400 MHz, DMSO-d₆): δ 7.81 (t. J=8.4 Hz, 1H, Ph),7.68-7.60 (m, 2H, CONH₂), 7.44-7.73 (m, 1H, Ph), 7.34-7.24 (m, 5H, Ph),6.91-6.84 (m, 2H, Ph), 4.64 (d, J=6.4 Hz, 2H, CH ₂Ph), 3.45-3.31 (m, 4H,CH ₂NCH ₂), 2.87-2.83 (m 2H, CHCH₃+NH), 2.54 (s, 3H, NCH ₃), 2.37 (s,3H, CH ₃), 1.30 (d, J=2.8 Hz, 3H, CH ₃CH).

Synthesis of1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamideFF14

To a solution of ethyl 2-oxocyclohexane-carboxylate (20.00 g, 117.50mmol) in EtOH (250.00 mL) was added urea (9.17 g, 152.76 mmol) at r.t.under N₂. The solution was stirred at r.t, for 5 min. Then MeONa (12.70g, 235.01 mmol) in MeOH (200 mL) was added in one portion. The whitesuspension was heated to 80° C., and stirred for 16 h. White solid wasprecipitated during stirring. TLC showed the reaction was completed.Then the suspension was filtered. The filter cake was washed with MTBE(50 mL*2) and then dried in vacuo to give the desired5,6,7,8-tetrahydroquinazoline-2,4(1,3H)-dione: (14.00 g, 65% yield, 90%¹H NMR purity) as a white powder. ¹HNMR (400 MHz, CD₃OD): δ 8.54 (br s,2H, CONH), 2.38 (m, 2H, CH₂CH ₂CCONH, 2.30 (m, 2H, CH₂CH ₂CNHCO), 1.71(m, 4H, CH₂CH ₂CH ₂CH₂).

A suspension of 5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (25.0 g,0.151 mol) in POCl₃ (100 mL) was heated to 120° C. and stirred for 2 h.TLC showed the reaction was complete. Then the mixture was concentratedin vacuo. The residue was dissolved in EtOAC (200 mL) and slowly pouredinto sat. NaHCO₃ (500 mL) at 0° C. Then the organic phase was separatedand aqueous phase was extracted with EtOAc (200 mL*2). The combinedorganic phase was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column (PE/EtOAc=20/1 to 10/1) togive 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (10.3 g, 99.9% HPLCpurity) as a white powder. ¹HNMR (300 MHz, CDCl₃): δ 2.89 (m, 2H. CH₂CH₂CCONH), 2.73 (m, 2H, CH₂CH ₂CNHCO), 1.88 (m, 4H, CH₂CH ₂CH ₂CH₂).

A mixture of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (1.0 g, 4.9mmol), (3-fluorphenyl)methanamine (796 mg, 6.37 mmol) and TEA (1.48 g,14.7 mmol) in MeCN (50 ml) was refluxed for 4 h under N₂. TLC showed thereaction was almost completed. The reaction was concentrated in vacuumand purified by column chromatography (PE/EA=10/1 to 5/1) to give thedesired 2-chloro-N-(3-fluorobenzyl)-5,6,7,8-tetrahydroquinazolin-4-amine(800 mg, 56% yield) as a white solid. LCMS (M+H⁺) m/z: Calcd: 292.10;Found: 292.1. A mixture of2-chloro-N-[(3-fluorophenyl)methyl]-5,6,7,8-tetrahydroquinazolin-4-amine(20 mg, 68.5 umol), 1H-indazole-4-carbonitrile (12 mg, 82.3 umol),Pd₂(dba)₃ (13 mg, 13.7 umol), Cs₂CO₃ (67 mg, 206 umol) and X-Phos (7 mg,13.7 umol) in dioxane (5 ml) was stirred at 100° C. for 4 h under N₂.TLC showed SM:TM=2:1. The reaction mixture was concentrated in vacuumand purified by column chromatography (PF/EA=10/1 to 5/1) to give1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carbonitrile(20 mg, 73%) as light yellow solid. LCMS (M+H+) m/z: Calcd: 399.17;Found: 399.2.

A mixture of1-[4-[(3-fluorophenyl)methylamino]-5,6,7,8-tetrahydroquinazolin-2-yl]indazole-4-carbonitrile(90 mg, 0.23 mmol), UHP (21.25 mg, 0.23 mmol) and K₂CO₃ (31.22 mg, 0.23mmol) in DMSO (10 ml) and H₂O (1 mL) was stirred at 20° C. for 16 hunder N₂. TLC showed the reaction was almost completed. The reaction wasconcentrated in vacuum and purified by prep-HPLC (H₂), MeCN. HCl) togive the desired1-(4-((3-Fluorobenzyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-1H-indazole-4-carboxamideFF14 (20 mg, 21.3%) as a white solid. LCMS (M+H⁺) m/z: Calcd: 417.18;Found: 417.2. ¹HNMR (400 MHz. DMSO-d₆): h 9.11 (s, 1H, CONH ₂), 8.91 (s,1H, 3-H of pyrazole), 8.30-8.26 (m, 2H, Ph), 7.87-7.85 (m, 1H, Ph), 7.71(s, 1H, CONH ₂), 7.56-7.54 (m, 1H, Ph), 7.43-7.42 (m, 2H, Ph), 7.09 (m,1H, CH₂NH), 4.88-4.87 (m, 2H, CH ₂NH), 2.82 (s, 2H, NCCH ₂), 1.84 (s,4H, CH₂CH ₂CH ₂CH₂).

Synthesis of1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamideFF15

To a mixture of compound 1 (13 g, 0.057 mol) in DCM (650 mL) was addedm-CPBA (73.69 g, 0.342 mol) portion wise. The resulting mixture wasstirred at r.t, for overnight. LCMS showed the reaction was completed.It was filtered and the filtrate was quenched with 5% Na₂S₂O₃ (500 mL),then sat. NaHCO₃ (500 mL) was added carefully. The organic phase wasseparated, washed with brine (300) mL), dried over Na₂SO₄, filtered andconcentrated to give crude compound 2. It was slurry with EA (100 mL)and filtered to give pure2,4-bis(methylsulfonyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine 2 (15 g,72%) as a white solid. LCMS (M+H⁺) m/z: Calcd: 293.03; Found: 293.0.

A mixture of compound 2 (10.0 g, 0.034 mol) in 10% NaOH (200 mL) wasrefluxed for 3 h. TLC showed the reaction was completed, it wasacidified with HCl (10%) until pH=2 and the solid was collected byfiltration to give6,7-dihydro-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione 3 (3.5 g, 60.8%)as a white solid. LCMS (M+H⁺) m/z: Calcd: 169.06; Found: 169.10.

A mixture of compound 3 (3.5 g, 0.021 mol) in POCl₃ (80 mL) was stirredat 100° C. for 12 h. TLC showed the reaction was completed, the mixturewas concentrated in vacuum to get a residue, it was diluted with DCM(500 mL) and poured into ice/water (200 mL). The organic layer wasseparated and washed with sat. NaHCO₃ (150 mL), brine (150 mL), driedover Na₂SO₄, filtered and concentrated to get a residue. It was purifiedby column chromatography (PE/EA=10/1) to give2,4-dichloro-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine 4 (2.2 g, 51.5%) asa white solid. LCMS (M+H⁺) m/z: Calcd: 204.99; Found: 205.1.

A mixture of intermediate 4 (1.0 g, 0.005 mol), amine 5 (0.671 g, 0.005mol) and TEA (0.985 g, 0.010 mol) in ACN (50 mL) was stirred at 90° C.for 12 h. LCMS showed 60% of the product was formed, the mixture wasconcentrated to give a residue which was stirred in EA (10 mL) andfiltered to give pure2-chloro-N-(3-fluorobenzyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-amine6 (0.4 g, 28%) as a white solid. LCMS (M+H⁺) m/z: Calcd: 294.08; Found:294.1. A mixture of intermediate 6 (100 mg, 0.340 mmol), compound 7(70.75 mg, 0.409 mmol), Pd₂(dba)₃ (93.53 mg, 0.102 mmol). X-Phos (63.70mg, 0.136 mmol) and K₂CO₃ (0.094 g, 0.68 mmol) in dioxane (30 mL) wasstirred at 100° C. for 2 h under N₂. TLC showed the reaction wascompleted. It was concentrated to get a residue, which was purified bycolumn chromatography (PE/EA=5/1) to give1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carbonitrile8 (0.11 g, 75.1%) as a yellow solid. LCMS (M+H⁺) m/z: Calcd: 431.16;Found: 431.2.

A mixture of compound 7 (90 mg, 0.209 mmol), acetaldehyde oxime (24.67mg, 0.418 mmol), PPh₃-resin (17 mg, 0.042 mmol) and Pd(OAc)₂ (9 mg) inEtOH/H₂O (5 mL, V/V=10/1) was stirred at 80° C. for 4 h. LCMS showed thereaction was completed. The reaction mixture was concentrated in vacuumto give a residue which was purified by prep-TLC to give1-(4-((3-Fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamideFF15 (0.044 g, 47%) as a white solid. LRMS (M+H⁺) m/z: Calcd: 449.17;Found: 449.30. ¹HNMR (400 MHz, DMSO-d₆): δ 8.76 (s, 1H, CONH₂),7.82-7.76 (m, 3H, Ph), 7.42-7.40 (m, 2H, Ph, CONH₂), 7.18-7.13 (m, 3H,Ph, NH), 7.04-7.02 (m, 1H, Ph), 4.61 (d, J=6.4 Hz, 2H, CH ₂Ph),4.32-4.30 (m, 2H, OCH ₂CH₂), 4.15 (s, 3H, OCH ₃), 2.02-1.98 (m, 2H,OCH₂CH₂CH ₂).

Synthesis of1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamideFF16

A mixture of compound 1 (50 mg, 0.170 mmol), compound 2 (29.24 mg, 0.204mmol), Pd₂(dba)₃ (46.67 mg, 0.051 mmol), X-Phos (31.85 g, 0.068 mmol)and Cs₂CO₃ (0.111 g, 0.34 mmol) in dioxane (10 mL) was stirred at 110°C. for 24 h, four same reactions was carried out in parallel. LCMSshowed the reaction was completed; four reactions were combined,concentrated to give a residue which was purified by columnchromatography (PE/EA=1/1) to give1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carbonitrile:3 (163 mg, 43%) as a white solid. LCMS (M+H⁺) m/z: Calcd: 401.15; Found:401.20.

A solution of compound 3 (123 mg, 0.307 mmol), UHP (0.144 g, 0.002 mol)and K₂CO₃ (0.042 g, 0.307 mmol) in DMSO/H₂O (10/1, 7 mL) was stirred at25° C. for 2 h. TLC and LCMS showed the reaction was completed. Themixture was poured into H₂O (30 mL) and extracted with EA (80 mL*2). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedto get a residue which was purified by prep-TLC to give desired1-(4-((3-Fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamideFF16 (53 mg, 41%) as a yellow solid. LCMS (M+H⁺) m/z: Calcd: 419.2;Found: 419.16. ¹HNMR (400 MHz, DMSO-d₆): δ 8.61 (s, 1H, Ph), 8.40 (d,J=8.4 Hz, 1H, Ph), 8.15-8.10 (m, 1H, CONH ₂), 7.71-7.67 (m, 2H, Ph),7.53-7.52 (m, 1H, CONH ₂), 7.40-7.36 (m, 2H, Ph), 7.36-7.25 (m, 2H,PhNH), 7.15-7.05 (m, 1H, Ph), 4.73 (d, J=6.0 Hz, 2H, PhCH ₂), 4.31 (t,J=4.4 Hz, 2H, OCH ₂CH₂CH₂), 2.02-1.98 (m, 2H, OCH₂CH₂CH ₂).

Biological Protocols

The in vitro and in vivo biological assays to determine the anti-cancerproperties of the fused pyrimidine compounds of the invention aresummarized above. The details of these protocols show how the assays arecarried out.

P97 Biochemical Assay Protocol

The p97 assay is an initial screening assay used to determine inhibitoryactivity of the fused pyrimidine compounds of the invention against thep97 complex. As discussed above, inhibition of activity of the p97proteosome complex can enable apoptosis and cause elimination ofneoplastic cells (cancer cells). The method follows that of Christiansonin Nat. Cell Biol., (2011) 14:93.

The Reagents Used for the p97 Assay Include:

Assay Buffer is a mixture of 50 mM TRIS pH 7.5, 20 mM MgCl₂, 0.02%TX-100, 1 mM DTT and 0.2% (v/v) Glycerol. The well plate is Platetype:Corning 3674, 384w plate. The identification kit is an ADP glo kit(Promega): stop buffer, detection reagent.

The Assay protocol is conducted as follows:

Serial dilute compound in DMSO in a 1:3.33-fold 10 point serialdilution.

in each well of 384w plate add the following reagents:

0.5 μL compound serial diluted in DMSO (Final Cone. 10%)

2 μL ATP (Final Conc.=20 uM, diluted in assay buffer)

2.5 μL p97 (Final Conc.=20 nM, diluted in assay buffer)

Incubate at 37 deg C. for 15 min.

Add 5 μL of stop buffer, incubate at RT for 40 min.

Add 10 μL of detection reagent, incubate at RT for 30 min.

Read luminescence on Envision plate reader.

Upon obtaining the data from the luminescence reading, the data may beanalyzed as follows:

Normalize luminescence data using no enzyme (full inhibition) and nocompound (no inhibition) controls. Plot normalized luminescence dataagainst log-transformed concentration values and fit to a sigmoidalcurve to determine IC50 values (done in Collaborative Drug Discoverysoftware).

Caco-2 Permeability Assay

This assay is designed as a model to indicate the permeability of afused pyrimidine compound of this invention through the gut-bloodbarrier. The result will yield indications of whether or not the fusedpyrimidine compound may be efficiently absorbed into the blood stream ofa patient. Efficient, effective absorption of an orally administereddrug determines in part its bioavailability. For the fused pyrimidinecompounds of the invention, this assay is a model to evaluate thebioavailability of the compounds as a result of their ability to passthrough biological barriers to entry into the physiological system ofthe patient.

The experimental goal of the Caco-2 assay is to measure directionalCaco-2 permeability of test compounds in cultured Caco-2 monolayer.

The test compounds are the fused pyrimidine compounds of the invention.

Set Up Instruments

-   -   Tissue culture CO₂ incubator with humidity control    -   Liquid handler    -   Orbital shaker    -   EVOM Epithelial Volt-ohmmeter fitted with planar electrodes        (World Precision Instruments, Sarasota, Fla.) required for        measuring transepithelial electrical resistance (TEER)    -   Bench top centrifuge with 96-well plate adaptor    -   Caco-2 cells (Human colorectal adenocarcinoma, ATCC #37-HTB,        passage 30-45)    -   Cells seeded onto PET membranes (1 μm pore size, 0.31 cm²        surface area) inside Falcon HTS multiwell Insert system using        24-well plates (Becton Dickinson plates, Part #351181, Fisher        Scientific, Inc.) at a density of 23,000 cells/well. Cells grown        20-23 days with medium changed every 2-3 days

Reagents

-   -   Ringers buffer solution (pH 7.4 at 25° C.)    -   Ringers buffer with 1% Methanol    -   Blk solution: Ringers buffer:Methanol=2:1 (v/v); 100% Methanol        including internal standard (IS); 10 mM stock dosing solution in        DMSO; 100 μM dosing solution in buffer.

Protocol Summary

-   -   Caco-2 permeability: 20-23 day/Passage 30-45    -   24-well format transwell: 0.31 cm2 surface area    -   Donor cone: 100 μM including 1% DMSO    -   A: 300 μL pH 7.4/B: 1200 μL, pH 7.4 Ringers buffer    -   Directionality: A B and B A (N=4)    -   Donor side sampling: 20 μL at beginning and end (90 min)    -   Receiver side sampling: 100 μL at 30, 50, 70, and 90 min    -   Incubation at 50 oscillations per minute, 37° C., 5% CO₂, 95%        humidity    -   Analysis: LC-UV, LC-MS, or LSC    -   Output: Peff (cm/sec)=(dX/dt)/(A*Co*60), dX/dt: transported        amount (mmole) versus time (minute) profile in the receiver        chamber; A: surface area (cm²); and Co: initial donor        concentration (pM)    -   Positive control: Atenolol and propranolol    -   Membrane integrity: TEER >200 Ocm²    -   Amount required: Approximately 1 mg or 100 μL of 10 mM test        compound in DMSO    -   Instruments: CO₂ incubator with humidity control, liquid        handler, epithelial volt-ohmmeter for TEER, Caco-2 cells (ATCC        #37-HTB), and 24-well insert plates (PET membranes, 1 μm pore        size, 0.31 cm² plates, Part #351181) surface area. Becton        Dickinson    -   Throughput: 6 compounds/2 Caco-2 plates/1 FTE/day

Preparation

TABLE 24 Preparation of Ringers with Glucose (Isotonic = 290 mOsm/kg),pH 7.4 Mass(g) Mass(g) Mass(g) Chemical Molecular Wt Concentration for 1L for 2 L for 4 L Ca SO₄ 2H₂O 172.2 1.25 mM 0.2152 0.4305 0.861 MgSO₄7H₂O 246.5 1.1 mM 0.2712 0.5423 1.0846 KCl 74.55 5 mM 0.3728 0.74551.491 Na₂HPO₄ 142.0 1.15 mM 0.1633 0.3266 0.6532 NaH₂PO₄ H₂O 138.0 0.3mM 0.0414 0.0828 0.1656 NaHCO₃ 84.01 25 mM 2.100 4.200 8.401Glucose(C₆H₁₂O₆) 180.2 25 mM 4.505 9.01 18.02 NaCl 58.44 110 mM 6.42812.86 25.71

Preparation of 4 L Solution

-   -   1. To 3.5 L distilled water, add Calcium Sulfate and Magnesium        Sulfate. Note: Add Calcium Sulfate and Magnesium Sulfate first        due to low solubility and add the remaining ingredients in the        order listed in Table 1.    -   2. Adjust the final volume of the solution to 4 L with distilled        water, with continuous stirring.    -   3. Adjust final solution to a pH of 7.4 using 1N HCl or 1N NaOH.    -   4. Make the buffer iso-osmotic using NaCl. Measure tonicity of        the solution using a tonometer. Given that an isotonic solution        is equivalent to 0.9% NaCl (290 mOsm/L).

Y={(290−x)/290}×9 mg×4000 mL, where y=NaCl required (in mg) to make thesolution isotonic and x=observed tonicity of solution (reported asmOsm/L).

Preparation of Dosing Solution in 15 mL PP Tube

-   -   1. 100 μM dosing solution in RG: 140 μL 10 mM stock+(14 mL−140        μL) RG

Preparation of Calibration in 96 Shallow Well.

-   -   1. Prepare 10 μM standard: 100 μL, of 100 μM dosing        solution+0.9 mi. Ringers with 1% Methanol.    -   2. Prepare analytical standard solutions 10, 5, 2, 1, 0.5, 0.2,        0.1,

TABLE 25 Preparation of analytical calibration in 96 shallow well 1 2 34 5 6 7 8 9 10 11 12 0 20 μL 20 μL 20 μL 20 μL 20 μL 20 μL 20 μL 40 μL100 μL 200 μL Source of 0.1 of 0.2 of 0.5 of 1 of 2 of 5 of 10 of 10 of10 of 10 solution μM μM μM μM μM μM μM μM μM μM 180 μL 180 μL 180 μL 180μL 180 μL 180 μL 180 μL 180 μL 160 μL 100 μL 0 1% MeOH in buffer Comp 1Blk 0.01 μM 0.02 μM 0.05 μM 0.1 μM 0.2 μM 0.5 μM 1 μM 2 μM 5 μM 10 μMComp 2 Comp 3

Transport Studies

Dosing and Sampling

1. Equilibrate both sides of the monolayers for 10 minutes withprewarmed (37° C.) drug-free Ringers buffer (300 μL apical side, 1,200μL basolateral side) supplemented with glucose (25 mM).

2. Measure TEER under 37° C. water bath conditions. Note: The TEER valueserves as a quality control check for monolayer integrity. At 21 dayspost-seeding, each Caco-2 cell monolayer should have a TEER value ofgreater than or equal to 2000×cm² and those not meeting this criteriaare not suitable for permeability evaluations.

3. When studying A to B transport: Fill basolateral side with 1,200 μLof Ringers buffer. Initiate transport experiments by transferring testdrug dosing solution (320 μL) to apical side.

4. When studying B to A transport: Fill apical side with 300 μL ofRingers buffer. Initiate transport experiments by transferring test drugdosing solution (1.220 μL) to basolateral side. Transport studies foreach direction (A to B, B to A) are performed in quadruplicate for eachtest drug.

5. Start timer after dosing last donor well.

6. Remove 20 μL aliquots from the donor wells at 0 minutes (D_(O)) andtransfer these aliquots to the donor site of the 96-well platecontaining 180 μL buffer with 1% Methanol. This step effectively dilutesthe D_(O) ten times.

7. Initiate transport studies by placing plate on orbital shakermaintained inside a prewarmed (37° C.) and humidified (5% CO₂)incubator. Studies are performed under stirring conditions at 50oscillations per minute.

8. Remove 100 μL aliquots from the receiver side of the monolayer at 30,50, 70, and 90 minutes postdosing and transfer these aliquots to thecorresponding 96-well sample plate (See Table 26). Replace with anequivalent volume of prewarmed buffer.

9. Remove 20 μL, aliquots from the donor side of the monolayer at 90minutes postdosing (D_(f)) and transfer these aliquots to a donor siteof a 96-well plate containing 180 μL Ringers buffer with 1% Methanol.This step effectively dilutes the D_(f) ten times.

10. Replace both sides of monolayer with fresh, drug-free, prewarmedRingers buffer (300 μL apical side, 1,200 μL basolateral side) andequilibrate for 10 minutes.

11. Measure TEER under 37° C. water bath conditions.

Sample Handling

The following steps refer to 96-well analytical plate for Caco-2, Table26.

1. Transfer 20 μL, of diluted D₀ and D_(f) to corresponding 96-wellsample plate with each well containing 80 μL buffer with 1% Methanol.This step effectively dilutes the samples five times further. Therefore,donor samples are diluted 50 times from their initial concentration.

2. Transfer 100 μL of analytical calibration (from 0 to 10 μM) to thesample plate row 1.

3. Add 50 μL Methanol including IS to all sample wells and mix(standards, samples, and Do and Dr).

4. Transfer 150 μL of Blk solution to the analytical plate row 2.

5. Seal the analytical plate with adhesive sealing film and storesamples with label at −80° C. for LC-UV or LC-MS analysis.

6. Analyze 20 μL aliquots of the individual permeability samples and thestandards using a suitable analytical instrument.

7. Peff=(dX/dt)/(A×C₀×60), where P_(eff) is the effective permeabilityin cm/sec. X=mass transported. A is the surface area (cm)² available fortransport, C₀ is the initial donor drug concentration (μM), and dX/dt isthe slope of the best fit line through the transported amount (mmole)versus time (min) profile in the receiver chamber.

TABLE 26 Analytical Plate for Caco-2 (96-well plate) 0 0.01 μM 0.02 μM0.05 μM 0.1 μM 1 μM 2 μM 5 μM 10 μM Blk Blk Blk Blk A to B 0.2 μM 0.5 μMB to A Blk Blk Blk Blk 1-30 2-30 3-30 4-30 5-30 6-30 7-30 8-30 1-50 2-503-50 4-50 5-50 6-50 7-50 8-50 1-70 2-70 3-70 4-70 5-70 6-70 7-70 8-701-90 2-90 3-90 4-90 5-90 6-90 7-90 8-90  1-Do  2-Do  3-Do  4-Do  5-Do 6-Do  7-Do  8-Do 1-Df 2-Df 3-Df 4-Df 5-Df 6-Df 7-Df 8-Df

Positive Control Data

Mean data in Table 27 represent the mean value from 12 separateinter-day experiments.

TABLE 27 P_(eff) (× E-6 cm/sec) in pH 7.4 Caco-2 A B B A Atenolol Mean 1.08  2.29 Range  0.69-1.80  1.69-2.68 Propranolol Mean 28.53 20.91Range 18.50-36.80 16.30-31.40

Mouse Liver Microsome Assay

The liver microsome assay is a model for studying the metabolicstability of the fused pyrimidine compounds of the invention. Metabolicstability is another aspect determining bioavailability. The facility ofa compound to be bioabsorbed into the blood stream as shown by theCaco-2 model indicates the degree to which an oral dose of the compoundwill reach the blood stream. The body efficiently metabolizes substancesto rid them from the body and/or to utilize them as nutrients. Thisaspect of bioavailability can be determined by such model studies asliver microsomal metabolism. Whether by oxidation, conjugation or anyother biological pathway, metabolism of a drug determines at least inpart the lifetime of the drug in the body.

The mouse liver microsome assay is a model designed to establish drughalf-life in vivo. The liver enzymes are responsible to conversion ofsubstances to materials that can be readily excreted by the body. Otherroutes for such metabolism include kidney metabolism, cellularmetabolism and the like.

In this protocol, the compound is combined with a liver microsomalpreparation (protein) and NADPH. The mixture is incubated and the rateof disappearance of the compound from the test solution is measured.

Measurement is made by screening for the compound concentration atspecified times using liquid chromatography in combination with massspectroscopy.

Concentrations of Reactants Ready for Formulation as the Test Solution;

Protein: 1.0 mg/ml

Compound: 1 um

Organic solvent: 0.4% DMSO

Medium: 0.1 M Potassium Phosphate (KB)

1 mM NADPH (sigma N1630, FW 833.3, make freshly)

Prepare test article (TA, i.e., a compound of the invention) bydissolving solid TA in DMSO to make a 0.25 mM solution

Amounts of Reactant Solutions to be Combined to Form the Test Solution:

423 ul KB (potassium phosphate) +25 ul MLM (20 mg/ml) (mouse livermicrosomal preparation) 448 ul  +2 ul Test compound (a fused pyrimidinecompound at 0.25 mM DMSO) +50 ul NADPH stock 10 mM, 10×) 500 ul

Test Protocol for Conducting the Assay

-   -   1. Add 423 ul KB to an 8-strip deep well tubes    -   2. Add 25 ul of MLM for condition 1    -   3. Place on ice, add 2 ul cmpds (250×stock in DMSO, stock at        0.25 mM)    -   4. Preincubate the reaction mixture at 37 C for 3 to 5 minutes        (shaking at 150 rpm)    -   5. Initiate reaction by adding 50 ul NADPH for condition 1    -   6. Add 50 ul KB for condition 2    -   7. An aliquot of samples of 100 ul were collected at 0, 15, 30,        and 60 min time point, and 200 ul of acetonitrile mixture        containing IS was added to quench the reaction.    -   8. Centrifuge for 10 min at 4000 rpm    -   9. The supernatant were injected for liquid chromatographic        tandem mass spectrometry (LC-MS/MS) analysis

Procedure of Protein Binding Using 96-Well Equilibrium dialyzer

Non-specific protein binding is another facet affecting bioavailabilityand effectiveness of a drug. To assay a compound for non-specificbinding, the compound is combined with human blood plasma and thesolution dialyzed against a membrane constructed to prevent passage oflarger molecules such as human plasma proteins but allow passage ofsmall molecules such as the compounds of the invention. Typically, suchmembranes allow passage of such compounds irrespective of their salt orneutral form. The dialysate (solution passing through the membrane) isexamined by liquid chromatography mass spectrometric techniques todetermine the identity and concentration of the compound present. Theconcentration of compound in the dialysate compared with theconcentration of compound combined with blood plasma indicates whetheror not non-specific protein binding has occurred.

Equipment and Reagent:

96-Well Equilibrium Dialyzer (made by: Harvard Apparatus)

Plate Rotator with DIALYZER plates secured in clamp fixtureBuffer: DPBS (gibco, 1×)Compound Concentration: 1 μM (˜0.5 in pg/mL) in Human Plasma

Procedure:

-   -   1. Seal the empty Sample Side well on the colored side with cap        strips.    -   2. Invert the plate and carefully pipet a volume of buffer, 200        μL equal to the sample volume into the wells on the Buffer Side        (clear frame) without touching the membranes by allowing the        liquid to flow along the inner side wall of each well.    -   3. Gently seal the filled buffer wells with cap strips.    -   4. Invert the plate and carefully remove the cap strips from the        sample side wells. Pipet desired samples, without touching the        membranes.    -   5. Reseal the sample wells with the cap strips.    -   6. Slide the assembled DIALYZER Plate into a Plate Rotator and        hand tighten the snobs. Turn on and allow rotating until        equilibrium has been reached (24 hours at 37 C), remove the        DIALYZER Plate from the Rotator.    -   7. After equilibrium has been reached, remove the DIALYZER Plate        from the rotator.    -   8. Carefully remove the cap strips from the Buffer Side of the        Plated (clear frame) and slowly pipet out the analysis samples        from the wells taking care not to touch or puncture the        membranes.

Samples will include control at 4 C and stability at 37 C samples in PBSand plasma.

MS Analysis:

-   -   Prepare standard range 5, 10, 50, 100, 500 and 1000 ng/mL in        Plasma Pipet 10 μL each of standard and sample into 40 μL of        blank buffer/blank plasma them (ratio: 1 plasma/4 DPBS), mix        them.    -   Add 200 μL of Is (internal standard) in ACN, mix well.    -   Centrifuge the samples and transfer supernatant solution for        LC/MS analysis.

The Cell Assay Protocol

The cellular assay provides information about the anti-neoplasticactivity of the compounds of the invention. The compounds are testedagainst cultured cancer cells to determine whether or not the compoundsof the invention are capable of intersecting with cancer cells tominimize or eliminate such cells. The assay involves establishingcolonies of such cells and then treating them with the test compoundunder specified conditions and analysis regima to determine results.

Day 1, Cell Plating to Establish Colonies of Cancer Cells

Cell Plating:

-   -   Seed cells ˜16 hrs prior to compound treatment    -   Plate 25 μL of A549 cells in every well of 384-well plate using        multidrop.    -   Two (2) black plates for IF at 2500 cells/well    -   Let plate sit at room temp for 10-15 minutes prior to putting in        incubator to    -   allow cells to stick in middle of plate.    -   One (1) white plate for viability at 500 cells/well.

Day 2 Treatment of Cultured Cells with Test Compounds

-   -   Treat Cells:    -   Serial dilute compounds with a 10 point 2-fold serial dilution        in DMSO to make 250× stock compound solution    -   Dilute compounds 1:125 in cell culture media to make a 2×        solution Add    -   25 μl of dilution compounds to cell plates in well duplicates        Put cells back in incubator (6 hr incubation for black plates,        72 hr incubation for white plates).

Fix/Stain Black Plates:

-   -   Incubate cells in black plates with compound at 37 deg C. for 6        hrs. add 15 μL of 16% Paraformaldehyde (PFA) directly into media        of each well, incubate at room temp for 5 min, flick plate and        wash in 50 μL of PBS block in 50 μL of Blocking Buffer for 30        minutes (can go up to several hours)    -   Blocking buffer: 1×PBS, 1% BSA, 0.3% Triton-X 100, Hoechst        (1:10,000) incubate in 25 μL of primary antibody in blocking        buffer at 4 deg C. over night

Primary Antibodies:

-   -   Plate A K48-Ub 1:20,000 (millipore 05-1307 Lot 2049282) Rabbit        CHOP/Gadd153 1:2,000 (SC-7351) Mouse    -   Plate B P53 1:2,000 (SC-6243) Rabbit p62/SQSTM1 1:2.000        (SC-28359) Mouse overnight at 4 deg C.

Secondary Antibodies:

-   -   AlexaFluor488 Goat anti-Rabbit 1:2,000 (Life Tech A11008)    -   AlexaFluor555 Goat anti-Mouse 1:2.000 (Life Tech A21422)

Day 3/4

-   -   Black Plate Staining (cont):    -   wash black plates 3× in 50 μL PBS (˜5 min each) incubate in 25l        of secondary antibody (1:2,000) in blocking buffer for 1-2 hrs        at room temp        (alexafluor488-anti-Rabbit/alexafluor555-anti-Mouse)    -   wash 4× in 50 μL PBS (˜5 min each)    -   leave plates in PBS for imaging    -   clean bottom of plates with 70% EtOH

Imaging:

-   -   Image plates in high content microscope with 405 nm, 488 nm and        555 nm filters

Data Analysis:

-   -   Nuclear counts and cellular intensities of each markers are        measured using Hoechst as a nuclear marker with an automated        image analysis protocol using Matlab software (Math Works)

Day 5

Viability Assay:

-   -   Thaw an aliquot of frozen cell titer glo (Promega G7572) at room        temperature.    -   Add 45 mL of NaCl/PBS solution to 5 ml of cell titer glo (10×).    -   Remove white plates from incubator, leave at room temp for 30        minutes.    -   Add 25 μl of diluted cell titer glo to each well.    -   Shake plate for >1 minute.    -   Incubate plate for >5 minutes to stabilize luminescence.    -   Luminescence is stable for up to 3 hours.    -   Read luminescence on plate reader

TABLE II Biological data for representative compounds of Formula I p97IC50 **** < 30 nM A549 CTG IC50 A549 K48 IC50 *** < 100 nM *** < 1 uM*** < 1 uM ** < 300 nM ** < 3 uM ** < 3 uM ID IUPAC name * < 1000 nm * <10 uM * < 10 uM FF03 1-(4-(benzylamino)-5,6,7,8- **** *** ***tetrahydroquinazolin-2-yl)-1H-indazole-4- carboxamide FF041-(4-(benzylamino)-7,8-dihydro-5H- ** NA NApyrano[4,3-d]pyrimidin-2-yl)-1H-indazole- 4-carboxamide FF053-(4-(benzylamino)-5,6,7,8- **** ** **tetrahydroquinazolin-2-yl)-2-methyl-1H- indole-7-carboxamide FF061-(-4-(benzylamino)-6,7-dihydro-5H- **** *** ***pyrano[2,3-d]pyrimidin-2-yl)-2-methyl- 1H-indole-4-carboxamide FF071-(4-(benzylamino)-5,6,7,8- **** *** ***tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2- methyl-1H-indole-4-carboxamideFF08 1-(4-(benzylamino)-5,6-dihydrofuro[2,3- *** ** **d]pyrimidin-2-yl)-2-methyl-1H-indole-4- carboxamide FF091-(4-((3-fluorobenzyl)amino)-6,7-dihydro- **** *** ***5H-pyrano[2,3-d]pyrimidin-2-yl)-2- methyl-1H-indole-4-carboxamide FF103-(4-benzylamino)-7,8-dihydro-5H- *** ** **pyrano[4,3-d]pyrimidin-2-yl)-2-methyl- 1H-indole-7-carboxamide FF111-(4-((3-fluorobenzyl)amino)-5-methyl- *** NA NA5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide FF121-(4-((3-fluorobenzyl)amino)-5-methyl- **** *** ***5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide FF131-(4-(benzylamino)-6,8-dimethyl-5,6,7,8- *** NA NAtetrahydropyrido[4,3-d]pyrimidin-2-yl)-2- methyl-1H-indole-4-carboxamideFF14 1-(4-((3-fluorobenzyl)amino)-5,6,7,8- *** ** NAtetrahydroquinazolin-2-yl)-1H-indazole-4- carboxamide FF151-4-((3-fluorobenzyl)amino)-6,7-dihydro- **** ** NA5H-pyrano[2,3-d]pyrimidin-2-yl)-2- methoxy-1H-benzo[d]imidazole-4-carboxamide FF16 1-(4-((3-fluorobenzyl)amino)-6,7-dihydro- **** * NA5H-pyrano[2,3-d-]pyrimidin-2-yl)-1H- indazole-4-carboxamide FF171-(4-(benzylamino)-5,6,7,8- **** *** NAtetrahydropyrido[2,3-d]pyrimidin-2-yl)-2- (hydroxymethyl)-1H-indole-4-carboxamide FF18 1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H- **** *** **cyclohepta[d]pyrimidin-2-yl)-2-methyl- 1H-indole-4-carboxamide FF191-(4-(benzylamino)-8-methyl-5,6,7,8- *** ** ***tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2- methyl-1H-indole-4-carboxamideFF20 1-(4-(benzylamino)-6,7,8,9-tetrahydro-5H- ** ** NApyrimido[4,5-d]azepin-2-yl)-2-methyl-4H- indole-4-carboxamide FF211-(4-(benzylamino)-5-methyl-5,6,7,8- **** *** ***tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2- methyl-1H-indole-4-carboxamideFF22 3-(4-((3-fluorobenzyl)amino)-7,8-dihydro- * NA NA5H-pyrano[4,3-d]pyrimidin-2-yl)-2- methylbenzofuran-7-carboxamide FF231-(4-(benzylamino)-5,6,7,8- **** ** **tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4- carboxamide FF241-(4-(benzylamino)-6,7-dihydro-5H- **** ** **pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide FF251-(4-((3-fluorobenzyl)amino)-5,6,7,8- **** ** **tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2- methyl-1H-indole-4-carboxamideFF26 1-(4((3-fluorobenzyl)amino)-5,6,7,8- **** ** **tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2- methyl-1H-indole-4-carboxamideFF27 3-(4-(benzylamino)-6,7-dihydro-5H *** ** **pyrano[2,3-d]pyrimidin-2-yl)-2-methyl- 1H-indole-7-carboxamide FF281-(4-(benzylamino)-6,7-dihydro-5H- *** ** **pyrano[2,3-d]pyrimidin-2-yl)-1H-indazole- 4-carboxamide FF291-(4-(benzylamino)-8-methyl-5,6,7,8- **** ** **tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2- methyl-1H-indole-4-carboxamideFF30 1-(4-((3,5-difluorobenzyl)amino)-6,7- **** ** **dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide FF312-(4-(aminomethyl)-2-methyl-1H-indol-1- ** NA NAyl)-N-benzyl-6,7-dihydro-5H-pyrano[2,3- d]pyrimidin-4-amine FF322-(aminomethyl)-1-(4-(benzylamino)-6,7- *** * *dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)- 1H-indole-4-carboxamide FF331-(4-(benzylamino)-5,6,7,8- * NA NAtetrahydropyrido[4,3-d]pyrimidin-2-yl)- 1H-inadazole-4-carboxamide FF341-(4-(benzylamino)-5,6,7,8- **** *** ***tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2- methyl-1H-indole-4-carboxamideFF35 3-(4-(benzylamino)-5,6,7,8- **** ** **tetrahydroquinazolin-2-yl)-2- methylbenzofuran-7-carboxamide FF36N-benzyl-2-(2-methyl-1H-indol-3-yl)- ** * *5,6,7,8-tetrahydroquinazolin-4-amine

Summary Statements

The inventions, examples, biological assays and results described andclaimed herein have may attributes and embodiments include, but hotlimited to, those set forth or described or referenced in thisapplication.

All patents, publications, scientific articles, web sites and otherdocuments and material references or mentioned herein are indicative ofthe levels of skill of those skilled in the art to which the inventionpertains, and each such referenced document and material is herebyincorporated by reference to the same extent as if it had beenincorporated verbatim and set forth in its entirety herein. The right isreserved to physically incorporate into this specification any and allmaterials and information from any such paten, publication, scientificarticle, web site, electronically available information, text book orother referenced material or document.

The written description of this patent application includes all claims.All claims including all original claims are hereby incorporated byreference in their entirety into the written description portion of thespecification and the right is reserved to physically incorporated intothe written description or any other portion of the application any anall such claims. Thus, for example, under no circumstances may thepatent be interpreted as allegedly not providing a written descriptionfor a claim on the assertion that the precise wording of the claim isnot set forth in haec verba in written description portion of thepatent.

While the invention has been described in conjunction with the detaileddescription thereof, the foregoing description is intended to illustrateand not limit the scope of the invention, which is defined by the scopeof the appended claims. Thus, from the foregoing, it will be appreciatedthat, although specific nonlimiting embodiments of the invention havebeen described herein for the purpose of illustration, variousmodifications may be made without deviating from the spirit and scope ofthe invention. Other aspects, advantages, and modifications are withinthe scope of the following claims and the present invention is notlimited except as by the appended claims.

The specific methods and compositions described herein arerepresentative of preferred nonlimiting embodiments and are exemplaryand not intended as limitations on the scope of the invention. Otherobjects, aspects, and embodiments will occur to those skilled in the artupon consideration of this specification, and are encompassed within thespirit of the invention as defined by the scope of the claims. It willbe readily apparent to one skilled in the art that varying substitutionsand modifications may be made to the invention disclosed herein withoutdeparting from the scope and spirit of the invention. The inventionillustratively described herein suitably may be practiced in the absenceof any element or elements, or limitation or limitations, which is notspecifically disclosed herein as essential. Thus, for example, in eachinstance herein, in nonlimiting embodiments or examples of the presentinvention, the terms “comprising”, “including”, “containing”, etc. areto be read expansively and without limitation. The methods and processesillustratively described herein suitably may be practiced in differingorders of steps, and that they are not necessarily restricted to theorders of steps indicated herein or in the claims.

The terms and expressions that have been employed are used as terms ofdescription and not of limitation, and there is no intent in the use ofsuch terms and expressions to exclude any equivalent of the featuresshown and described or portions thereof, but it is recognized thatvarious modifications are possible within the scope of the invention asclaimed. Thus, it will be understood that although the present inventionhas been specifically disclosed by various nonlimiting embodimentsand/or preferred nonlimiting embodiments and optional features, any andall modifications and variations of the concepts herein disclosed thatmay be resorted to by those skilled in the art are considered to bewithin the scope of this invention as defined by the appended claims.

The invention has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any subject matter from the genus, regardless of whether or notthe excised material is specifically recited herein.

It is also to be understood that as used herein and in the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise, for example, the term “Xand/or Y” means “X” or “Y” or both “X” and “Y”, and the letter “s”following a noun designates both the plural and singular forms of thatnoun. In addition, where features or aspects of the invention aredescribed in terms of Markush groups, it is intended, and those skilledin the art will recognize, that the invention embraces and is alsothereby described in terms of any individual member and any subgroup ofmembers of the Markush group, and the right is reserved to revise theapplication or claims to refer specifically to any individual member orany subgroup of members of the Markush group.

1-26. (canceled)
 27. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a fused pyrimidine compound ofFormula I

or a pharmaceutically acceptable salt thereof, wherein: A is NR⁵ or O;HET is a 5:6 bicyclic aromatic group having one or two nitrogens in the5 member ring and is selected from the group consisting of Formula H5and Formula H10

Wherein: R¹ is selected from the group consisting of halogen, carboxyl,carboxamido, —CH₂NH₂, sulfonyl hydroxide, sulfonamido, amino, mono, dialkyl amino of 1 to 6 carbons, nitrile, —C(O)NH— alkyl having 1 to 6carbons in the alkyl group, —CH₂OH, and alkoxy of 1 to 6 carbons; R⁵ ishydrogen or alkyl of 1 to 4 carbons Each R⁶ is independently selectedfrom hydrogen, halogen, linear, branched or cyclo alkyl of 1 to 6carbons, carboxyl, carboxamido, —CH₂NH₂, sulfonyl hydroxide,sulfonamido, amino, mono, di alkyl amino of 1 to 6 carbons, nitrile,—C(O)NH-alkyl having 1 to 6 carbons in the alkyl group, perfluoroalkylof 1 to 3 carbons, or alkoxy of 1 to 6 carbons; R⁷ is hydrogen or alkylof 1 to 4 carbons; Ar is phenyl or fluorophenyl.
 28. A pharmaceuticalcomposition according to according to claim 27 wherein R⁵ of A ishydrogen or methyl.
 29. A pharmaceutical composition according to claim27 wherein R¹ is selected from the group consisting of carboxyl,carboxamido, sulfonyl hydroxide, sulfonamido, N-alkyl carboxamido,N,N-dialkylcarboxamido, N-alkylsulfonamido, N,N-dialkylsulfonamido, andwherein each alkyl group is independently selected from 1 to 4 carbons.30. A pharmaceutical composition according to claim 27 wherein R¹ iscarboxyl, carboxamido, sulfonyl hydroxide, sulfonamido, N-methylcarboxamido or N-methyl sulfonamido.
 31. A pharmaceutical compositionaccording to claim 27 wherein Ar is an unsubstituted phenyl.
 32. Apharmaceutical composition according to claim 27, wherein A is NH.
 33. Apharmaceutical composition according to claim 27, wherein A is O.
 34. Apharmaceutical composition according to claim 27 comprising apharmaceutically acceptable carrier and a fused pyrimidine compound ofFormula I selected from any one of the following names or a salt orhydrate thereof:1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-1H-indazole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-(hydroxymethyl)-1H-,indole-4-carboxamide,1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-(hydroxymethyl)-1H-indole-4-carboxamide,1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,2-(4-(aminomethyl)-2-methyl-1H-indol-1-yl)-N-benzyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-4-amine,2-(aminomethyl)-1-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-1H-indole-4-carboxamide,3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-((3-fluorobenzyl)amino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-((3-fluorobenzyl)amino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-((3-fluorobenzyl)amino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-(benzylamino)-5-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-(benzylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-(benzylamino)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-(benzylamino)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-benzo[d]imidazole-4-carboxamide,1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,3-(4-((3-fluorobenzyl)amino)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-((3-fluorobenzyl)amino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide,3-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-7-carboxamide.35. The compound of claim 34 having the name:1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-(3-fluorobenzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(3-fluorobenzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-(3-fluorobenzylamino)-7,8-dihydro-6H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,or1-(4-(3-fluorobenzylamino)-7,8-dihydro-6H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide.36. The compound of claim 35 having the name1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideor1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide.37. The compound of claim 36 having the name1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide.38. A method for treatment of cancer, comprising administering to ahuman patient, who has a cancer selected from the group consisting ofcolorectal cancer, non-small cell lung cancer, multiple myeloma, skincancer, breast cancer, liver cancer, kidney cancer, head and neck cancerand leukemia, an effective amount of the pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a fused pyrimidinecompound of Formula IA1 or formula IB1

or a pharmaceutically acceptable salt thereof, wherein: A is NH or O; R¹is CO₂H or CONH₂; R⁶ is methyl or methoxy; Ar is phenyl or fluorophenyl.39. A method for treatment of cancer in a human patient in need of suchtreatment according to claim 38 wherein the pharmaceutical compositionis administered orally at a dose of up to 2000 mg of the fusedpyrimidine compound per day and the patient's serum concentration of thefused pyrimidine compound is monitored to adjust the dosage or timing ofadministration or both.
 40. A method according to claim 38 wherein thecancer is multiple myeloma, colorectal cancer or non-small cell lungcancer.
 41. A method according to claim 38 wherein the fused pyrimidinecompound of Formula IA1 or IB1 is selected from any one of the compoundshaving the following names:1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-((3-fluorobenzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-(3-fluorobenzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(3-fluorobenzylamino)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide,1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy-1H-indole-4-carboxamide,1-(4-(3-fluorobenzylamino)-7,8-dihydro-6H-pyrano[2,3-d]pyrimidin-2-yl)-2-methylH-indole-4-carboxamide, or1-(4-(3-fluorobenzylamino)-7,8-dihydro-6H-pyrano[2,3-d]pyrimidin-2-yl)-2-methoxy1H-indole-4-carboxamide.
 42. A method according to claim 41 wherein thefused pyrimidine compound has the name1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamideor1-(4-(benzylamino)-7,8-dihydro-6H-pyrano[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide.43. A method according to claim 42 wherein the fused pyrimidine compoundhas the name1-(4-((benzyl)amino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide.44. A method of decreasing Valosin Containing Protein-Proteosome pathwayactivity in a patient comprising administering to the patient aneffective amount of a pharmaceutical composition comprising apharmaceutically acceptable carrier and a fused pyrimidine compound ofFormula IA1 or formula IB1

or a pharmaceutically acceptable salt thereof, wherein: A is NH or O; R¹is CO₂H or CONH₂; R⁶ is methyl or methoxy: Ar is phenyl or fluorophenyl.45. A method according to claim 44 wherein the patient is a human.